TW201928063A - Methods for treating HEPCIDIN-mediated disorders - Google Patents

Methods for treating HEPCIDIN-mediated disorders Download PDF

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TW201928063A
TW201928063A TW107134726A TW107134726A TW201928063A TW 201928063 A TW201928063 A TW 201928063A TW 107134726 A TW107134726 A TW 107134726A TW 107134726 A TW107134726 A TW 107134726A TW 201928063 A TW201928063 A TW 201928063A
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卡克爾拉合
N 達維拉而傑曼德哈夫
珍 艾斯克特凱瑟林
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Abstract

Methods for treating hepcidin-mediated disorders are provided.

Description

用於治療海帕西啶(HEPCIDIN)介導之病症之方法Method for treating HEPCIDIN-mediated conditions

肽激素海帕西啶在全身鐵恆定中起主要作用。Hentze等人,Cell 142:24-38 (2010)。已知海帕西啶表現受TMPRSS6 基因之產物間質蛋白酶-2影響，該間質蛋白酶-2為II型跨膜絲胺酸蛋白酶。已顯示TMPRSS6 基因之常見變異體與鐵狀態相關，Benyamin等人,Nature Genetics 41(11):1173-1175 (2009)，其中已顯示在海帕西啶表現及血液血紅素含量方面，rs855791 SNP (2321G→A；A736V)與天然存在的變型相關。 海帕西啶表現亦涉及於人類鐵病症(Pietrangelo,J. Hepatology 54:173-181 (2011))及慢性疾病貧血(ACD)(亦稱為發炎貧血(AI))中。ACD流行於患有慢性感染、自體免疫疾病、癌症及慢性腎病(CKD)之患者中。Sun等人,Am. J. Hematol . 87(4):392-400 (2012)。 在此項技術中需要治療海帕西啶介導之病症之方法。The peptide hormone hypaxidine plays a major role in systemic iron homeostasis. Hentze et al., Cell 142: 24-38 (2010). It is known that hypaxidine performance is affected by the product of the TMPRSS6 gene, interstitial protease-2, which is a type II transmembrane serine protease. Common variants of the TMPRSS6 gene have been shown to be related to iron status, Benyamin et al., Nature Genetics 41 (11): 1173-1175 (2009), which has shown rs855791 SNP ( 2321G → A; A736V) is associated with naturally occurring variants. Hypaxidine performance is also implicated in human iron disorders (Pietrangelo, J. Hepatology 54: 173-181 (2011)) and chronic disease anemia (ACD) (also known as inflammatory anemia (AI)). ACD is prevalent in patients with chronic infections, autoimmune diseases, cancer, and chronic kidney disease (CKD). Sun et al., Am. J. Hematol . 87 (4): 392-400 (2012). There is a need in the art for a method for treating a hepaxidine-mediated condition.

已證實在患有海帕西啶介導之病症(包括慢性疾病貧血及海帕西啶介導之細胞毒性)之患者中，降低之IL-6信號傳導提供臨床效益，但僅在具有TMPRSS6 rs855791主要對偶基因之至少一個複本的彼等患者中，其中在具有升高之IL-6含量之患者中具有最大作用。 因此，在第一態樣中，提供治療海帕西啶介導之病症之方法。該等方法包含向患有海帕西啶介導之病症之患者投與治療有效量之IL-6拮抗劑，該患者已經確定具有TMPRSS6 rs855791 SNP處之主要對偶基因之至少一個複本。在第一系列之實施例中，先前已確定患者具有TMPRSS6 rs855791主要對偶基因之至少一個複本。在另一系列實施例中，方法進一步包含確定患者具有TMPRSS6 rs855791主要對偶基因之至少一個複本之早前步驟。通常，患者具有升高之治療前血清IL-6含量。在一些實施例中，患者具有升高之治療前血清CRP含量。 在各種實施例中，海帕西啶介導之病症為慢性疾病貧血。 在一些貧血實施例中，患者為男性且治療前血紅素(Hb)含量小於14 g/dl；治療前Hb含量小於13 g/dl；治療前Hb含量小於12 g/dl；或治療前Hb含量小於11 g/dl。在一些貧血實施例中，患者為女性且治療前Hb含量小於12 g/dl；治療前Hb含量小於11 g/dl；治療前Hb含量小於10 g/dl；或治療前Hb含量小於9 g/dl。 在一些貧血實施例中，患者為男性且治療前血容比小於40%，小於35%或為30-34%。在一些實施例中，患者為女性且治療前血容比小於36%、小於35%、小於34%、小於33%、小於32%或小於31%。在一些實施例中，女性患者之治療前血容比為26-29%。 在各種貧血實施例中，患者已接受至少一次紅血球生成刺激劑(ESA)之治療前投與。在某些實施例中，患者已接受至少一次ESA之治療前投與且具有正常Hb含量或正常血容比。在各種實施例中，患者已接受至少一次鐵補充劑之治療前投與。在某些實施例中，患者已接受至少一次鐵補充劑之治療前投與且具有正常Hb含量或正常血容比。在各種實施例中，患者已接受至少一次血液或紅血球濃厚液之治療前輸注。在某些實施例中，患者已接受至少一次血液或紅血球濃厚液之治療前輸注且具有正常Hb含量或正常血容比。 在各種貧血實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使患者之Hb含量增加而高於治療前含量之時間期。在各種實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使患者之血容比增加而高於治療前含量之時間期。在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以在不降低患者之Hb含量的情況下使患者之ESA劑量減少而低於治療前即刻存在之含量的時間期。在某些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以在不降低患者之血容比的情況下使患者之ESA劑量減少而低於治療前即刻存在之含量的時間期。 在各種實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續以下的時間期：足以使患者之ESA劑量相較於治療前ESA劑量減少至少10%、使患者之ESA劑量相較於治療前ESA劑量減少至少20%、使患者之ESA劑量相較於治療前ESA劑量減少至少30%、使患者之ESA劑量相較於治療前ESA劑量減少至少40%，或使患者之ESA劑量相較於治療前ESA劑量減少至少50%。 在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以逆轉功能性鐵缺乏之時間期。 在一系列實施例中，海帕西啶介導之病症為慢性疾病為慢性腎病(CKD)Z 慢性疾病貧血。 在一些CKD實施例中，患者具有KDOQI 1期慢性腎病、KDOQI 2期慢性腎病、KDOQI 3期慢性腎病、KDOQI 4期慢性腎病或KDOQI 5期慢性腎病。在特定實施例中，患者具有KDOQI 5期慢性腎病。 在一些CKD實施例中，患者患有心腎症候群(CRS)。在特定實施例中，患者患有4型CRS。在某些實施例中，患者已接受至少一次治療前透析治療。 在一些CKD實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續相較於年齡匹配且疾病匹配之歷史對照足以降低心血管(CV)死亡率之時間期。 在各種實施例中，海帕西啶介導之病症為慢性疾病為慢性發炎疾病之慢性疾病貧血。 在一些實施例中，慢性發炎疾病為類風濕性關節炎(RA)。在某些實施例中，患者之治療前DAS28得分大於5.1。在一些實施例中，患者之治療前DAS28得分為3.2至5.1。在特定實施例中，患者之治療前DAS28得分小於2.6。在所選擇實施例中，患者之治療前RA為中度活動性至重度活動性的。 在一些RA實施例中，患者已接受至少一次甲胺喋呤之治療前投與。在一些實施例中，患者已接受至少一次TNFα拮抗劑之治療前投與。在所選實施例中，TNFα拮抗劑選自由以下組成之群:依那西普(etanercept)、阿達木單抗(adalimumab)、英利昔單抗(infliximab)、賽妥珠單抗(certolizumab)及戈利木單抗(golimumab)。 在一些RA實施例中，患者已接受至少一次IL-6拮抗劑之治療前投與。在某些實施例中，治療前IL-6拮抗劑為托珠單抗(tocilizumab)或托法替尼(tofacitinib)。 在一較佳系列之實施例中，治療IL-6拮抗劑為MEDI5117。 在各種實施例中，海帕西啶介導之病症慢性疾病選自由以下組成之群之慢性疾病貧血：幼年期特發性關節炎、僵直性脊椎炎、斑狀牛皮癬、牛皮癬性關節炎、發炎性腸病、克羅恩氏病(Crohn's disease)及潰瘍性結腸炎。 在一些實施例中，海帕西啶介導之病症為慢性疾病為癌症之慢性疾病貧血。在某些實施例中，癌症選自由以下組成之群：實體腫瘤、小細胞肺癌、非小細胞肺癌、血液癌、多發性骨髓瘤、白血病、慢性淋巴細胞白血病(CLL)、慢性骨髓性白血病(CML)、淋巴瘤、霍奇金氏淋巴瘤(Hodgkin's lymphoma)及肝腺瘤。 在一些實施例中，海帕西啶介導之病症為慢性疾病貧血，其中慢性疾病為慢性感染。 在一些實施例中，海帕西啶介導之病症為慢性疾病貧血，其中慢性疾病為充血性心臟衰竭(CHF)。 在一些實施例中，海帕西啶介導之病症為鐵難治性缺鐵性貧血(IRIDA)。 在一些實施例中，海帕西啶介導之病症為急性冠狀動脈症候群。在特定實施例中，患者在第一次投與IL-6拮抗劑之前之60天內、在第一次投與IL-6拮抗劑之前之30天內、在第一次投與IL-6拮抗劑之前之48小時內或在第一次投與IL-6拮抗劑之前之24小時內已罹患心肌梗塞(MI)。 在一些急性冠狀動脈症候群實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續相較於治療前程度足以改良心肌收縮性之時間期。在一些急性冠狀動脈症候群實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續相較於治療前程度足以提高心臟射血分數之時間期。在一些急性冠狀動脈症候群實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續相較於治療前程度足以降低心臟纖維化之時間期。 在一些實施例中，海帕西啶介導之病症為卡斯爾曼氏病(Castleman's Disease)。 在另一態樣中，提供用於改良對海帕西啶介導之病症之治療的方法。方法包含向患有海帕西啶介導之病症之患者中斷IL-6拮抗劑之投與，其中已確定該患者針對TMPRSS6 rs855791次要對偶基因為同型接合的。 在另一態樣中，提供藉由中斷為低效之療法而改良對海帕西啶介導之病症之治療的方法，從而在不喪失治療功效之情況下降低副作用且降低成本。該等方法包含向患有海帕西啶介導之病症之患者中斷IL-6拮抗劑之投與，其中已確定該患者針對TMPRSS6 rs855791次要對偶基因為同型接合的。在一系列實施例中，先前已確定患者針對TMPRSS6 rs855791次要對偶基因為同型接合的。在另一系列實施例中，方法進一步包含確定患者針對TMPRSS6 rs855791次要對偶基因為同型接合之早前步驟。在典型實施例中，患者具有升高之治療前血清IL-6含量。在各種實施例中，患者具有升高之治療前血清CRP含量。在各種實施例中，患者患有選自本文中部分5.4.1中所描述之彼等病症之海帕西啶介導之病症。在某些實施例中，患者患有慢性疾病貧血。 實例2、3及5中所呈現之資料表明在具有升高之治療前IL-6含量且具有TMPRSS6 主要對偶基因之至少一個複本、甚至不存在貧血之個體中，IL-6拮抗劑提供治療效益。因此，在另一態樣中，提供用於治療無慢性發炎貧血之患者中的IL-6介導之發炎病症之方法。該等方法包含向患有IL-6介導之發炎病症之個體、通常人類患者投與治療有效量之IL-6拮抗劑，其中該患者不患有貧血，且其中已確定該個體具有TMPRSS6 rs855791主要對偶基因之至少一個複本。在第一系列之實施例中，先前已確定個體具有TMPRSS6 rs855791主要對偶基因之至少一個複本。在另一系列實施例中，方法進一步包含確定個體具有TMPRSS6 rs855791主要對偶基因之至少一個複本之早前步驟。通常，方法肯定地排除治療針對TMPRSS6 rs855791次要對偶基因為同型接合之個體。通常，患者具有升高之治療前血清IL-6含量。 在治療方法中之任一者之特定實施例中，患者具有升高之治療前血清IL-6含量。在某些實施例中，患者之治療前血清IL-6含量大於2.5 pg/ml、大於5 pg/ml、大於7.5 pg/ml、大於10 pg/ml或大於12.5 pg/ml。 在各種實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使患者血清中之游離IL-6含量降低而低於治療前含量之時間期。在特定實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使游離IL-6含量相較於治療前含量降低至少10%、相較於治療前含量降低至少20%或相較於治療前含量降低至少50%之時間期。 在治療方法中之任一者之特定實施例中，患者具有升高之治療前C反應蛋白(CRP)含量。在某些實施例中，患者之治療前CRP含量大於2 mg/ml、大於3 mg/ml、大於5 mg/ml、大於7.5 mg/ml或甚至大於10 mg/ml。 在各種實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使患者之CRP含量降低而低於治療前含量之時間期。在特定實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使患者之CRP含量相較於治療前含量降低至少50%之時間期。 在治療方法中之任一者之特定實施例中，使用TaqMan®即時PCR分析，已確定患者具有TMPRSS6 rs855791主要對偶基因之至少一個複本。 在治療方法中之任一者之實施例中，IL-6拮抗劑為抗IL-6抗體或其抗原結合片段或衍生物。 在某些實施例中，抗IL-6抗體或抗原結合片段或衍生物對人類IL-6之結合性具有小於100 nM、小於50 nM、小於10 nM或小於1 nM之KD 。在某些實施例中，抗IL-6抗體或抗原結合片段或衍生物在靜脈內投與之後具有至少7天、至少14天、至少21天或至少30天之消除半衰期。 在各種抗體實施例中，IL-6拮抗劑為全長單株抗IL-6抗體，諸如IgG1或IgG4抗體。 在所選實施例中，抗IL-6抗體或抗原結合片段或衍生物為完全人類的。在一些實施例中，抗IL-6抗體或抗原結合片段或衍生物為人類化的。 在目前較佳之實施例中，抗IL-6抗體或抗原結合片段或衍生物包含MED5117之所有六個可變區CDR。在一些此等實施例中，抗體包含MED5117之VH及VL。且在特定實施例中，抗體為MED5117。 在各種實施例中，抗IL-6抗體或抗原結合片段或衍生物包含選自由以下組成之群的抗體之所有六個可變區CDR：司妥昔單抗(siltuximab)、格里林祖單抗(gerilimzumab)、思魯庫單抗(sirukumab)、克拉雜奇單抗(clazakizumab)、奧諾奇單抗(olokizumab)、艾思莫單抗(elsilimomab)、VX30 (VOP-R003；Vaccinex)、EB-007 (EBI-029；Eleven Bio)、ARGX-109 (ArGEN-X)、FM101 (Femta Pharmaceuticals，Lonza)及ALD518/BMS-945429 (Alder Biopharmaceuticals，Bristol-Myers Squibb)。 在一些實施例中，抗IL-6抗體或抗原結合片段或衍生物包含來自選自由以下組成之群的抗體之重鏈V區及輕鏈V區：司妥昔單抗、格里林祖單抗、思魯庫單抗、克拉雜奇單抗、奧諾奇單抗、VX30 (VOP-R003；Vaccinex)、EB-007 (EBI-029；Eleven Bio)、ARGX-109 (ArGEN-X)、FM101 (Femta Pharmaceuticals，Lonza)及ALD518/BMS-945429 (Alder Biopharmaceuticals，Bristol-Myers Squibb)。在特定實施例中，抗IL-6抗體為選自由以下組成之群的抗體：司妥昔單抗、格里林祖單抗、思魯庫單抗、克拉雜奇單抗、奧諾奇單抗、VX30 (VOP-R003；Vaccinex)、EB-007 (EBI-029；Eleven Bio)、ARGX-109 (ArGEN-X)、FM101 (Femta Pharmaceuticals，Lonza)及ALD518/BMS-945429 (Alder Biopharmaceuticals，Bristol-Myers Squibb)。 在一些實施例中，抗IL-6抗體或抗原結合片段或衍生物為選自由以下組成之群的抗體：司妥昔單抗、格里林祖單抗、思魯庫單抗、克拉雜奇單抗、奧諾奇單抗、VX30 (VOP-R003；Vaccinex)、EB-007 (EBI-029；Eleven Bio)、ARGX-109 (ArGEN-X)、FM101 (Femta Pharmaceuticals，Lonza)及ALD518/BMS-945429 (Alder Biopharmaceuticals，Bristol-Myers Squibb)。在特定實施例中，抗IL-6抗體為選自由以下組成之群的抗體：司妥昔單抗、格里林祖單抗、思魯庫單抗、克拉雜奇單抗、奧諾奇單抗、VX30 (VOP-R003；Vaccinex)、EB-007 (EBI-029；Eleven Bio)、ARGX-109 (ArGEN-X)、FM101 (Femta Pharmaceuticals，Lonza)及ALD518/BMS-945429 (Alder Biopharmaceuticals，Bristol-Myers Squibb)。 在各種實施例中，IL-6拮抗劑為單域抗體、VHH奈米抗體、Fab或scFv。 在各種實施例中，IL-6拮抗劑為抗IL-6R抗體或其抗原結合片段或衍生物。在某些實施例中，抗IL-6R抗體、抗原結合片段或衍生物為托珠單抗或夫巴利珠單抗(vobarilizumab)。 在各種實施例中，IL-6拮抗劑為JAK抑制劑。在特定實施例中，JAK抑制劑選自由以下組成之群：托法替尼(Xeljanz)、得森替尼(decernotinib)、盧佐替尼(ruxolitinib)、尤帕達替尼(upadacitinib)、巴瑞替尼(baricitinib)、斐哥替尼(filgotinib)、來妥替尼(lestaurtinib)、帕瑞替尼(pacritinib)、皮非替尼(peficitinib)、INCB-039110、ABT-494、INCB-047986及AC-410。 在各種實施例中，IL-6拮抗劑為STAT3抑制劑。 在IL-6拮抗劑為抗體或抗原結合片段或衍生物之一些實施例中，IL-6拮抗劑非經腸投與。在特定實施例中，IL-6拮抗劑經皮下投與。 在IL-6拮抗劑為JAK抑制劑或STAT3抑制劑之一些實施例中，其中經口投與IL-6拮抗劑。Reduced IL-6 signalling has been shown to provide clinical benefit in patients with hippoxidine-mediated disorders, including anemia of chronic disease and hippoxidine-mediated cytotoxicity, but only in patients with TMPRSS6 Of those patients with at least one replica of the primary dual gene, the greatest effect was found in patients with elevated IL-6 content. Therefore, in a first aspect, a method is provided for treating a hepaxidine-mediated disorder. The methods include administering a therapeutically effective amount of an IL-6 antagonist to a patient suffering from a hepaxidine -mediated condition, the patient having been identified to have at least one copy of the major dual gene at the TMPRSS6 rs855791 SNP. In the first series of examples, it has been previously determined that the patient has at least one copy of the TMPRSS6 rs855791 major dual gene. In another series of embodiments, the method further comprises an earlier step of determining that the patient has at least one replica of the TMPRSS6 rs855791 major dual gene. Generally, patients have elevated pre-treatment serum IL-6 levels. In some embodiments, the patient has an elevated pre-treatment serum CRP content. In various embodiments, the hypaxidine-mediated condition is anemia of chronic disease. In some examples of anemia, the patient is male and has a pre-treatment hemoglobin (Hb) content of less than 14 g / dl; pre-treatment Hb content is less than 13 g / dl; pre-treatment Hb content is less than 12 g / dl; or pre-treatment Hb content Less than 11 g / dl. In some examples of anemia, the patient is a female and the Hb content before treatment is less than 12 g / dl; the Hb content before treatment is less than 11 g / dl; the Hb content before treatment is less than 10 g / dl; or the Hb content before treatment is less than 9 g / dl. In some examples of anemia, the patient is male and the pre-treatment blood volume ratio is less than 40%, less than 35%, or 30-34%. In some embodiments, the patient is female and the pre-treatment hematocrit is less than 36%, less than 35%, less than 34%, less than 33%, less than 32%, or less than 31%. In some embodiments, the pre-treatment hematocrit of a female patient is 26-29%. In various examples of anemia, the patient has received at least one pre-treatment administration of a red blood cell stimulating agent (ESA). In certain embodiments, the patient has been administered at least one pre-treatment of ESA and has a normal Hb content or normal blood volume ratio. In various embodiments, the patient has received at least one pre-treatment administration of an iron supplement. In certain embodiments, the patient has been administered at least one pre-treatment with an iron supplement and has a normal Hb content or a normal blood volume ratio. In various embodiments, the patient has received at least one pre-treatment infusion of blood or red blood cell concentrate. In certain embodiments, the patient has received at least one pre-treatment infusion of blood or red blood cell concentrate and has a normal Hb content or a normal hematocrit. In various examples of anemia, a dose of an IL-6 antagonist is administered on a time schedule and for a period of time sufficient to increase the patient's Hb content above the pre-treatment level. In various embodiments, one dose of the IL-6 antagonist is administered on a time schedule and for a period of time sufficient to increase the patient's blood volume ratio above the pre-treatment level. In some embodiments, a dose of an IL-6 antagonist is administered on a time schedule and for a time sufficient to reduce the patient's ESA dose without reducing the patient's Hb content to a time below the level present immediately before treatment period. In some embodiments, a dose of an IL-6 antagonist is administered on a time schedule and continued to be sufficient to reduce the patient's ESA dose without reducing the content of the patient's ESA immediately before treatment Time period. In various embodiments, a dose of an IL-6 antagonist is administered on a time schedule for a period of time sufficient to reduce the patient's ESA dose by at least 10% compared to the pre-treatment ESA dose, and enable the patient's ESA dose Reduce the ESA dose of patients by at least 20% compared to before treatment, reduce the patient's ESA dose by at least 30%, reduce the patient's ESA dose by at least 40%, or reduce the patient's The ESA dose was reduced by at least 50% compared to the ESA dose before treatment. In some embodiments, one dose of the IL-6 antagonist is administered over a period of time and for a period of time sufficient to reverse functional iron deficiency. In a series of embodiments, the hepaxidine-mediated condition is a chronic disease that is chronic kidney disease (CKD) Z chronic disease anemia. In some CKD embodiments, the patient has KDOQI stage 1 chronic kidney disease, KDOQI stage 2 chronic kidney disease, KDOQI stage 3 chronic kidney disease, KDOQI stage 4 chronic kidney disease, or KDOQI stage 5 chronic kidney disease. In a particular embodiment, the patient has KDOQI stage 5 chronic kidney disease. In some CKD embodiments, the patient has a cardio-renal syndrome (CRS). In a particular embodiment, the patient has type 4 CRS. In certain embodiments, the patient has received at least one pre-treatment dialysis treatment. In some CKD embodiments, one dose of the IL-6 antagonist is administered on a time course and is sufficient to reduce the cardiovascular (CV) mortality time period compared to age-matched and disease-matched historical controls. In various embodiments, the hypaxidine-mediated condition is a chronic disease anemia in which the chronic disease is a chronic inflammatory disease. In some embodiments, the chronic inflammatory disease is rheumatoid arthritis (RA). In certain embodiments, the patient's pre-treatment DAS28 score is greater than 5.1. In some embodiments, the patient's pre-treatment DAS28 score is 3.2 to 5.1. In a particular embodiment, the patient's pre-treatment DAS28 score is less than 2.6. In selected embodiments, the patient's pre-treatment RA is moderately active to severely active. In some RA embodiments, the patient has been administered at least one pre-treatment of methotrexate. In some embodiments, the patient has received at least one pre-treatment administration of a TNFα antagonist. In selected embodiments, the TNFα antagonist is selected from the group consisting of etanercept, adalimumab, infliximab, certolizumab, and Golimumab. In some RA embodiments, the patient has received at least one pre-treatment administration of an IL-6 antagonist. In certain embodiments, the pre-treatment IL-6 antagonist is tocilizumab or tofacitinib. In a preferred series of embodiments, the therapeutic IL-6 antagonist is MEDI5117. In various embodiments, the chronic disease mediated by hypaxidine is selected from the group consisting of chronic disease anemia consisting of: juvenile idiopathic arthritis, ankylosing spondylitis, plaque psoriasis, psoriasis arthritis, inflammation Bowel disease, Crohn's disease and ulcerative colitis. In some embodiments, the hypaxidine-mediated disorder is a chronic disease anemia in which the chronic disease is cancer. In certain embodiments, the cancer is selected from the group consisting of: solid tumors, small cell lung cancer, non-small cell lung cancer, blood cancer, multiple myeloma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia ( CML), lymphoma, Hodgkin's lymphoma, and hepatic adenoma. In some embodiments, the hypaxidine-mediated condition is anemia of chronic disease, wherein the chronic disease is a chronic infection. In some embodiments, the hypaxidine-mediated condition is anemia of chronic disease, wherein the chronic disease is congestive heart failure (CHF). In some embodiments, the hypaxidine-mediated condition is iron-refractory iron deficiency anemia (IRIDA). In some embodiments, the hypaxidine-mediated condition is an acute coronary syndrome. In a specific embodiment, the patient is within 60 days before the first administration of the IL-6 antagonist, within 30 days before the first administration of the IL-6 antagonist, and within the first administration of IL-6 Myocardial infarction (MI) has been developed within 48 hours before the antagonist or within 24 hours before the first administration of the IL-6 antagonist. In some examples of acute coronary syndromes, a dose of an IL-6 antagonist is administered on a time course and for a period of time sufficient to improve myocardial contractility compared to before treatment. In some examples of acute coronary syndromes, a dose of an IL-6 antagonist is administered on a time course and for a period of time sufficient to increase the cardiac ejection fraction compared to the pre-treatment level. In some examples of acute coronary syndromes, a dose of an IL-6 antagonist is administered on a time course and for a period of time sufficient to reduce cardiac fibrosis compared to before treatment. In some embodiments, the hypaxidine-mediated disorder is Castleman's Disease. In another aspect, methods are provided for improving the treatment of a hepaxidine-mediated disorder. The method includes discontinuing the administration of an IL-6 antagonist to a patient with a hepaxidine-mediated condition, wherein the patient has been identified to be homozygous for the TMPRSS6 rs855791 minor dual gene. In another aspect, a method for improving the treatment of a Hypaxidine-mediated condition by discontinuing it as an ineffective therapy is provided, thereby reducing side effects and costs without losing therapeutic efficacy. These methods include discontinuing the administration of an IL-6 antagonist to a patient with a hepaxidine -mediated condition, where the patient has been identified as being homozygous for the TMPRSS6 rs855791 minor dual gene. In a series of embodiments, the patient has previously been determined to be homozygous for the TMPRSS6 rs855791 minor dual gene. In another series of embodiments, the method further comprises an earlier step of determining that the patient is homozygous for the TMPRSS6 rs855791 minor dual gene. In a typical embodiment, the patient has an elevated pre-treatment serum IL-6 content. In various embodiments, the patient has an elevated pre-treatment serum CRP content. In various embodiments, the patient has a hepaxidine-mediated condition selected from the group consisting of those described in Section 5.4.1 herein. In certain embodiments, the patient has chronic disease anemia. The data presented in Examples 2, 3, and 5 indicate that IL-6 antagonists provide therapeutic benefit in individuals with elevated pre-treatment IL-6 levels and at least one replica of the TMPRSS6 major dual gene, even without anemia . Therefore, in another aspect, a method is provided for treating an IL-6-mediated inflammatory condition in a patient without chronic inflammatory anemia. The methods include administering a therapeutically effective amount of an IL-6 antagonist to an individual with a IL-6 mediated inflammatory condition, typically a human patient, wherein the patient does not suffer from anemia, and wherein the individual has been identified to have TMPRSS6 rs855791 At least one copy of the primary dual gene. In a first series of examples, it has previously been determined that an individual has at least one copy of the TMPRSS6 rs855791 major dual gene. In another series of embodiments, the method further comprises an earlier step of determining that the individual has at least one copy of the TMPRSS6 rs855791 major dual gene. Generally, the method definitely excludes treating individuals who are homozygous for the TMPRSS6 rs855791 minor dual gene. Generally, patients have elevated pre-treatment serum IL-6 levels. In a particular embodiment of any of the methods of treatment, the patient has an elevated pre-treatment serum IL-6 content. In certain embodiments, the patient's pre-treatment serum IL-6 content is greater than 2.5 pg / ml, greater than 5 pg / ml, greater than 7.5 pg / ml, greater than 10 pg / ml, or greater than 12.5 pg / ml. In various embodiments, one dose of the IL-6 antagonist is administered on a time course and for a period of time sufficient to reduce the free IL-6 content in the patient's serum to less than the pre-treatment content. In a specific embodiment, one dose of the IL-6 antagonist is administered on a schedule and is continued to reduce the free IL-6 content by at least 10% compared to the pre-treatment content and at least 20% compared to the pre-treatment content. Or a time period when the content is reduced by at least 50% compared to before treatment. In a particular embodiment of any of the methods of treatment, the patient has an elevated pre-treatment C-reactive protein (CRP) content. In certain embodiments, the patient's pre-treatment CRP content is greater than 2 mg / ml, greater than 3 mg / ml, greater than 5 mg / ml, greater than 7.5 mg / ml, or even greater than 10 mg / ml. In various embodiments, one dose of the IL-6 antagonist is administered over a time period and for a period of time sufficient to reduce the patient's CRP content below the pre-treatment level. In a particular embodiment, one dose of the IL-6 antagonist is administered over a period of time and for a period of time sufficient to reduce the patient's CRP content by at least 50% compared to the pre-treatment content. In a specific embodiment of any of the methods of treatment, using TaqMan® real-time PCR analysis, it has been determined that the patient has at least one copy of the TMPRSS6 rs855791 major dual gene. In an embodiment of any of the methods of treatment, the IL-6 antagonist is an anti-IL-6 antibody or an antigen-binding fragment or derivative thereof. In certain embodiments, the anti-IL-6 antibody or antigen-binding fragment or derivative thereof having less than 100 nM, less than 50 nM, less than 10 nM, or less than 1 nM of K D for human IL-6 binding of. In certain embodiments, the anti-IL-6 antibody or antigen-binding fragment or derivative has an elimination half-life of at least 7 days, at least 14 days, at least 21 days, or at least 30 days after intravenous administration. In various antibody embodiments, the IL-6 antagonist is a full-length monoclonal anti-IL-6 antibody, such as an IgG1 or IgG4 antibody. In selected embodiments, the anti-IL-6 antibody or antigen-binding fragment or derivative is fully human. In some embodiments, the anti-IL-6 antibody or antigen-binding fragment or derivative is humanized. In a currently preferred embodiment, the anti-IL-6 antibody or antigen-binding fragment or derivative comprises all six variable region CDRs of MED5117. In some of these embodiments, the antibody comprises VH and VL of MED5117. And in a specific embodiment, the antibody is MED5117. In various embodiments, the anti-IL-6 antibody or antigen-binding fragment or derivative comprises all six variable region CDRs selected from the group consisting of antibodies: siltuximab, grelimuzumab Anti-gerilimzumab, sirukumab, clazakizumab, olokizumab, elsilimomab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), ARGX-109 (ArGEN-X), FM101 (Femta Pharmaceuticals, Lonza), and ALD518 / BMS-945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb). In some embodiments, the anti-IL-6 antibody or antigen-binding fragment or derivative comprises a heavy chain V region and a light chain V region from an antibody selected from the group consisting of: stuximab, grilimuzumab Antibody, siluzumab, clazacizumab, onochomazumab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), ARGX-109 (ArGEN-X), FM101 (Femta Pharmaceuticals, Lonza) and ALD518 / BMS-945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb). In a specific embodiment, the anti-IL-6 antibody is an antibody selected from the group consisting of: stuximab, grelimizumab, siluzumab, clazazumab, onochizumab Antibody, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), ARGX-109 (ArGEN-X), FM101 (Femta Pharmaceuticals, Lonza), and ALD518 / BMS-945429 (Alder Biopharmaceuticals, Bristol) -Myers Squibb). In some embodiments, the anti-IL-6 antibody or antigen-binding fragment or derivative is an antibody selected from the group consisting of: stuximab, grilimuzumab, silukumab, clazaci MAb, Onochomab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), ARGX-109 (ArGEN-X), FM101 (Femta Pharmaceuticals, Lonza), and ALD518 / BMS -945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb). In a specific embodiment, the anti-IL-6 antibody is an antibody selected from the group consisting of: stuximab, grelimizumab, siluzumab, clazazumab, onochizumab Antibody, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), ARGX-109 (ArGEN-X), FM101 (Femta Pharmaceuticals, Lonza), and ALD518 / BMS-945429 (Alder Biopharmaceuticals, Bristol) -Myers Squibb). In various embodiments, the IL-6 antagonist is a single domain antibody, a VHH nanobody, a Fab, or a scFv. In various embodiments, the IL-6 antagonist is an anti-IL-6R antibody or an antigen-binding fragment or derivative thereof. In certain embodiments, the anti-IL-6R antibody, antigen-binding fragment or derivative is tocilizumab or vobalizumab. In various embodiments, the IL-6 antagonist is a JAK inhibitor. In a specific embodiment, the JAK inhibitor is selected from the group consisting of tofacitinib (Xeljanz), decernotinib, ruxolitinib, upadacitinib, barbados Baricitinib, Figotinib, Lestaurtinib, Pacritinib, Peficitinib, INCB-039110, ABT-494, INCB-047986 And AC-410. In various embodiments, the IL-6 antagonist is a STAT3 inhibitor. In some embodiments where the IL-6 antagonist is an antibody or antigen-binding fragment or derivative, the IL-6 antagonist is administered parenterally. In a particular embodiment, the IL-6 antagonist is administered subcutaneously. In some embodiments where the IL-6 antagonist is a JAK inhibitor or a STAT3 inhibitor, the IL-6 antagonist is administered orally.

相關申請案之交叉參考 本申請案主張2015年7月31日申請之美國臨時申請案第62/199,434號及2015年12月17日申請之美國臨時申請案第62/268,788號之優先權，其中之每一者以全文引用之方式併入。5.1實驗結果之概述 肽激素海帕西啶在全身鐵恆定中起主要作用。Hentze等人,Cell 142:24-38 (2010)。已知海帕西啶表現受TMPRSS6 基因之產物間質蛋白酶-2影響，該間質蛋白酶-2為II型跨膜絲胺酸蛋白酶。已顯示TMPRSS6 基因之常見變異體與鐵狀態相關，Benyamin等人,Nature Genetics 41(11):1173-1175 (2009)，其中已顯示在海帕西啶表現及血液血紅素含量方面，rs855791 SNP (2321G→A；A736V)與天然存在的變型相關。海帕西啶表現亦涉及於人類鐵病症(Pietrangelo,J. Hepatology 54:173-181 (2011))及慢性疾病貧血(ACD)(亦稱為發炎貧血(AI))中。ACD流行於患有慢性感染、自體免疫疾病、癌症及慢性腎病(CKD)之患者中。Sun等人,Am. J. Hematol . 87(4):392-400 (2012)。 為判定TMPRSS6 rs855791 SNP處之基因型是否預測末期腎病中之貧血程度，結合新確定之SNP基因分型來分析先前在患有慢性腎病之患者之臨床研究中收集的資料。由於海帕西啶表現亦由IL-6調節，Casanovas等人,PLOS Computational Biol. 10(1):e1003421 (2014)，進一步分析資料以判定血清IL-6含量是否可預測末期腎病中之貧血程度。 如實例1中所描述且如圖1中所展示，在具有TMPRSS6 rs855791 SNP處之主要對偶基因之至少一個複本的患者中，基礎貧血程度-量測為臨床上滴定之EPO劑量-僅與IL-6含量相關。在此等患者中，更高之血清IL-6含量與更高之所需EPO劑量相關(圖1B)。相反，具有次要對偶基因之兩個複本之患者的貧血程度不與血清IL-6含量相關(圖1A)。 類似地，在具有TMPRSS6 SNP rs855791處之主要對偶基因之至少一個複本的患者中，總存活率僅與IL-6含量相關。在具有TMPRSS6 rs855791主要對偶基因之至少一個複本之個體中，存活率成反比地與血清IL-6含量相關，其中血清IL-6含量之最高位中之患者比IL-6含量之最低位中之彼等患者具有統計學上顯著更壞的存活率(圖2B)。相反，針對rs855791處之次要對偶基因為同型接合之患者之總存活率不受IL-6含量影響(圖2A)。 不意欲受理論束縛，在具有TMPRSS6 主要對偶基因之至少一個複本之患者中，血清IL-6之增加可促進海帕西啶表現增加，從而增加貧血。增加之死亡風險為失調之鐵代謝、所得貧血及/或增加之紅血球生成刺激劑(諸如EPO，經投與以用於治療)劑量之結果。此等相關性提昇了以下可能性：降低之IL-6含量或IL-6信號傳導可降低貧血，減少所需EPO劑量，且增加患有慢性腎病之患者之存活率，但僅在具有TMPRSS6 rs855791主要對偶基因之至少一個複本之彼等患者中，且在具有升高之血清IL-6含量之彼等患者中具有最大作用。 為判定在患有急性而非慢性之疾病之患者中TMPRSS6 rs855791基因型是否影響IL-6敏感性，實例2中吾人結合新確定之SNP基因分型來分析先前在因急性冠狀動脈症候群住院之患者之臨床研究中收集的資料。 針對TMPRSS6 rs855791 SNP次要對偶基因(A)為同型接合之個體之死亡不與IL-6之變型相關(圖4A)。然而，回應於心肌梗塞後個體中之升高之IL-6含量，主要對偶基因(G)之一或兩個複本賦予更高之各種原因之死亡(圖4B)。因此，TMPRSS6 調節心肌梗塞後之IL-6介導之死亡風險。 亦評估TMPRSS6 基因型對IL-6介導之心臟衰竭風險之影響。在針對次要對偶基因(A)為同型接合之個體之心臟衰竭不與IL-6之變型相關(圖5A)。然而，回應於心肌梗塞後個體中之升高之IL-6含量，TMPRSS6 之G對偶基因賦予更高之心臟衰竭速率(圖5B)。因此，TMPRSS6 調節心肌梗塞後之IL-6介導之心臟衰竭風險。 來自實例2之資料表明TMPRSS6 基因型、IL-6含量及不利臨床結果之間的相關性不限於患有慢性腎病之患者。不意欲受理論束縛，在具有TMPRSS6 主要對偶基因之至少一個複本之患者中，血清IL-6之增加可促進海帕西啶表現增加，隨後心肌細胞中鐵之螯合作用增加，繼之以鐵介導之細胞毒性。此等相關性提昇了以下可能性：降低之IL-6含量或IL-6信號傳導可降低患有急性冠狀動脈症候群之患者之心臟衰竭及死亡，但僅在具有TMPRSS6 rs855791主要對偶基因之至少一個複本之彼等患者中，且在具有升高之血清IL-6含量之彼等患者中具有最大作用。 雖然實例1及2中所觀測之相關性強烈表明在具有TMPRSS6 rs855791主要對偶基因之至少一個複本、升高之IL-6含量及貧血或海帕西啶介導之細胞毒性之患者中，降低之IL-6介導之信號傳導應提供臨床效益，但所觀測相關性不能證明因果關係。因此，在實例3中，人類誘導之多能性幹(iPS)細胞心肌細胞經工程化以僅表現TMPRSS6 rs855791主要對偶基因或次要對偶基因，且活體外經測試。 海帕西啶表現藉由BMP6/SMAD及IL-6/STAT信號傳導路徑調節，其中BMP及IL-6兩者經由其各別受體起作用以促進海帕西啶表現增加。Casanovas等人,PLOS Comp. Biol . 10(1):e1003421 (2014)。活體外用信號傳導路徑-重組BMP2及IL-6-之促效劑或單獨用BMP2之促效劑處理主要對偶基因及次要對偶基因iPS心肌細胞，以模型化IL-6含量(或信號傳導)降低之臨床干預。不用促效劑處理對照iPS細胞。在正常氧張力(常氧)下且亦在模擬低氧隨後模擬再充氧(再灌注)之條件下量測細胞死亡率。 圖6A展示當細胞在正常氧含量下處理時之結果。僅表現TMPRSS6 rs855791次要對偶基因(「736V次要對偶基因」)之iPS心肌細胞不顯著受IL-6信號傳導之消除影響(「n.s.」)：相較於用BMP2+IL-6進行之處理，當用BMP2處理細胞時，量測為錐蟲藍陽性細胞之百分比之細胞死亡率不顯著降低。相反，當消除IL-6信號傳導時，表現TMPRSS6 rs855791主要對偶基因之iPS心肌細胞展示統計學上顯著更低之細胞死亡。 圖6B展示當細胞經歷低氧隨後經歷再充氧時之結果。相較於常氧條件，低氧/再充氧對iPS心肌細胞有毒性，其中相較於在常氧條件下殺死之約20%對照細胞，約40百分比之主要及次要對偶基因對照細胞經殺死(與圖6A相比較)。相對於此增加之背景毒性，次要對偶基因iPS心肌細胞不顯著受IL-6信號傳導之消除影響：相較於用BMP2+IL-6進行之處理，當單獨用BMP2處理細胞時，細胞死亡率不顯著降低。相反，當消除IL-6信號傳導時，表現TMPRSS6 rs855791主要對偶基因之iPS心肌細胞展示統計學上顯著更低之細胞死亡。 此等資料增強了自實例1及實例2中之臨床試驗資料之後hoc分析所得出之推斷：IL-6信號傳導之降低有效地降低表現TMPRSS6 rs855791主要對偶基因之心肌細胞中之IL-6介導之毒性，但在僅表現次要對偶基因之心肌細胞中不如此。不意欲受理論束縛，促進主要對偶基因iPS心肌細胞中之毒性增加之IL-6可起因於海帕西啶表現之IL-6介導之增加，隨後細胞中增加之鐵螯合作用，繼之以鐵介導之細胞毒性。 患有慢性腎病之患者，諸如入選於在實例1中分析之MIMICK研究中之彼等患者，常常罹患減弱之心臟功能，其為總死亡率之主要促成者。初次慢性腎病後之此二次心臟損傷稱為4型心腎症候群(4型CRS)。為直接測試抗IL-6療法是否作為治療在具有TMPRSS6 rs855791主要對偶基因之至少一個複本之CRS4患者中有效，如藉由實例1及3中之資料所表明，吾人使用基因型地類似於針對TMPRSS6 rs855791主要對偶基因為同型接合之人類之大鼠的CRS4模型。 治療4週後，與同型對照組相比，處理組-用抗IL-6抗體治療之組及用標準護理ACE抑制劑療法培哚普利治療之組-展示統計學上顯著增加之射血分數程度(圖8D) (p＜0.001)。在治療4週後量測之抗IL-6及標準護理組中之類似射血分數程度展示抗IL-6療法具有與ACE抑制劑等效之功效。圖9展示在保持心肌收縮性方面，抗IL-6療法亦具有與ACE抑制劑等效之有效性。圖10A-10C表明抗IL-6療法同樣在降低心臟纖維化方面有效。 此等資料表明在基因型地類似於針對TMPRSS6 rs855791主要對偶基因為同型接合之人類之動物的心腎症候群活體內模型中，用抗IL-6劑進行之治療有效地降低心臟損傷且恢復功能。 類似地，實例2及3中之資料表明降低之IL-6含量或IL-6信號傳導可降低患有急性冠狀動脈症候群之患者之心臟衰竭及死亡，但僅在具有TMPRSS6 rs855791主要對偶基因之至少一個複本之彼等患者中，且在具有升高之血清IL-6含量之彼等患者中具有最大作用。 進行研究以確定在基因型地類似於針對TMPRSS6 rs855791主要對偶基因為同型接合之人類之小鼠中，急性心肌梗塞後抗IL-6療法之作用。 圖11A及11B展示來自活體內模型之資料，在該模型中，在基因型地類似於針對TMPRSS6 rs855791主要對偶基因為同型接合之人類之小鼠中誘導心肌梗塞。對照組不接受療法。實驗組用抗鼠類IL-6抗體治療。圖11A展示相較於對照，用抗IL-6進行之治療在射血分數方面提供統計學上顯著之提高。圖11B展示相較於對照，用抗IL-6進行之治療在量測為心臟縮短分數之收縮性方面提供統計學上顯著之提高。此等資料表明在心肌梗塞後立即給出之抗IL-6療法提高了基因型地類似於具有TMPRSS6 rs855791主要對偶基因之人類患者之嚙齒動物中左心室的功能恢復。 總之，實驗資料表明在患有海帕西啶介導之病症(諸如貧血或海帕西啶介導之細胞毒性)之患者中，降低IL-6信號傳導之治療干預將提供臨床效益，但僅在具有TMPRSS6 rs855791主要對偶基因之至少一個複本之彼等患者中，其中在具有升高之IL-6含量之患者中具有最大作用。 因此，如下文進一步描述，在第一態樣中，提供治療海帕西啶介導之病症之方法。該等方法包含向患有海帕西啶介導之病症之患者投與治療有效量之IL-6拮抗劑，該患者已經確定具有TMPRSS6 rs855791 SNP處之主要對偶基因之至少一個複本。在第二態樣中，提供用於改良對海帕西啶介導之病症之治療的方法，該方法包含向患有海帕西啶介導之病症之患者中斷IL-6拮抗劑之投與，其中已確定該患者針對TMPRSS6 rs855791次要對偶基因為同型接合的。治療藉由中斷為低效之療法而改良，從而在不喪失治療功效的情況下降低副作用且降低成本。在另一態樣中，提供用於治療無慢性發炎貧血之患者中的IL-6介導之發炎病症之方法，該等方法包含向患者投與治療有效量之IL-6拮抗劑，該患者患有IL-6介導之發炎病症，不患有貧血，且已確定個體具有TMPRSS6 rs855791主要對偶基因之至少一個複本。 5.2 定義 除非另外定義，否則本文所使用之所有技術及科學術語具有熟習本發明所屬領域者通常理解的含義。如本文中所使用，以下術語具有下文中賦予其之含義。 「海帕西啶 」意謂與以NCBI寄存編號NP_066998(「海帕西啶前蛋白」)或其生物活性片段提供之胺基酸序列具有至少約85%或大於85%之胺基酸一致性的多肽。例示性海帕西啶生物活性包括結合且降低鐵輸出通道運鐵素之含量、抑制鐵轉運、抑制腸道鐵吸收且抑制鐵自巨噬細胞及肝臟之釋放。下文提供例示性海帕西啶前蛋白胺基酸序列：參考上文序列，海帕西啶以各種形式存在，包括呈前激素原(preprohormone) (胺基酸25-84)、前激素(胺基酸25-84)形式，及稱為海帕西啶-25 (胺基酸60-84)、海帕西啶-22 (胺基酸63-84)及海帕西啶-20 (胺基酸65-84)之成熟形式。 「海帕西啶介導之病症 」為海帕西啶表現促成病症或其症狀中之任一者之病因之任何病症。自一觀測可已知、可懷疑或可推斷海帕西啶對病因之貢獻，該觀測為相較於針對TMPRSS6 rs855791 SNP次要對偶基因為同型接合之患有病症之患者，IL-6拮抗劑之投與在具有TMPRSS6 rs855791 SNP主要對偶基因之至少一個複本的患有病症之患者中提供更大的治療效益。海帕西啶介導之病症在下文進一步描述於部分5.4.1中。 「跨膜蛋白酶絲胺酸 6 (TMPRSS6 ) 多肽 」意謂與以NCBI寄存編號NP_001275929提供之胺基酸序列具有至少約85%或大於85%之胺基酸一致性且具有絲胺酸蛋白酶活性的多肽或其片段。TMPRSS6 多肽，亦稱為間質蛋白酶-2 (MT2)，分解鐵調素調節蛋白且抑制骨形態生成蛋白信號傳導。下文提供在位置736處具有丙胺酸(736A)之例示性TMPRSS6 胺基酸序列：下文提供在位置736處具有纈胺酸(736V)之例示性TMPRSS6 胺基酸序列：「 TMPRSS6 核酸分子 」意謂編碼TMPRSS6 多肽(間質蛋白酶-2；MT2)之聚核苷酸。例示性TMPRSS6 核酸分子序列以NCBI寄存編號NM_001289000提供。下文提供在核苷酸位置2321處具有G (「G對偶基因」；「主要對偶基因」)之TMPRSS6 核酸序列： 下文提供在核苷酸位置2321處具有A之TMPRSS6 核酸序列： 「變異體 」意謂因一或多個核苷酸或一或多個胺基酸而不同於參考序列之聚核苷酸或多肽序列。例示性TMPRSS6 變異體為TMPRSS6 (A736V)，由SNP rs855791 (G→A)引起。 「單核苷酸 多形現象 」或「SN P」意謂天然存在之DNA序列變異體，其中基因組中之單核苷酸在生物物種之成員之間或在個體中之配對染色體之間不同。SNP可用作變異對偶基因之遺傳標記。在一個實施例中，TMPRSS6 SNP為rs855791。 「rs855791 」意謂人類TMPRSS6 基因中之單核苷酸多形現象(SNP)，2321G→A，在由TMPRSS6 基因編碼之間質蛋白酶-2 (MT2)之催化區中引起丙胺酸至纈胺酸之取代(A736V)。人類群體中具有最高頻率之對偶基因(主要對偶基因)為2321G，編碼736A。人類群體中具有最低頻率之對偶基因(次要對偶基因)為2321A，編碼736V。 「異型接合 」意謂染色體基因座具有兩個不同的對偶基因。在本文中所描述之方法之一個實施例中，異型接合係指以下基因型：在其中一個對偶基因具有編碼在胺基酸位置736處具有丙胺酸之TMPRSS6 多肽之TMPRSS6 核酸序列(例如在TMPRSS6 核酸分子之核苷酸位置2321處具有G或C) (rs855791主要對偶基因)，且另一對偶基因具有編碼在胺基酸位置736處包含纈胺酸之TMPRSS6 多肽之變異TMPRSS6 核酸序列(例如在TMPRSS6 核酸分子之核苷酸位置2321處具有A或T) (rs855791次要對偶基因)。 「同型接合 」意謂染色體基因座具有兩個相同的對偶基因。在本文中所描述之方法之某些實施例中，同型接合係指以下基因型：在其中兩個對偶基因具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之TMPRSS6 核酸序列(例如在TMPRSS6 核酸分子之核苷酸位置2321處具有G或C) (rs855791同型接合之主要對偶基因)。在一些實施例中，同型接合係指以下基因型：在其中兩個對偶基因具有編碼在胺基酸位置736處包含纈胺酸之TMPRSS6 多肽之TMPRSS6 核酸序列(例如在TMPRSS6 核酸分子之核苷酸位置2321處具有A或T) (rs855791同型接合之次要對偶基因)。 「確定患者具有 TMPRSS6 rs855791 主要對偶基因之至少一個複本 」包括(但不限於)進行分析以確定患者具有TMPRSS6 rs855791主要對偶基因之至少一個複本；對分析排序以確定患者具有TMPRSS6 rs855791主要對偶基因之至少一個複本；規定分析以確定患者具有TMPRSS6 rs855791主要對偶基因之至少一個複本；以其他方式引導或控制分析經進行以確定患者具有TMPRSS6 rs855791主要對偶基因之至少一個複本；及查閱TMRSS6 基因型分析資料或蛋白質或核酸序列資料以確定患者具有TMPRSS6 rs855791主要對偶基因之至少一個複本。 「介白素 6 (IL-6) 」或「IL-6 多肽 」意謂與以NCBI寄存編號NP_000591提供之胺基酸序列具有至少約85%或大於85%之胺基酸一致性且具有IL-6生物活性之多肽或其片段。IL-6為具有多種生物功能之多效性細胞激素。例示性IL-6生物活性包括免疫刺激及促炎性活性。下文提供例示性IL-6胺基酸序列：「介白素 6 (IL-6) 核酸 」意謂編碼介白素6 (IL-6)多肽之聚核苷酸。例示性介白素6 (IL-6)核酸序列以NCBI寄存編號NM_000600提供。下文提供以NCBI寄存編號NM_000600之例示性序列。 「介白素 6 受體 (IL-6R) 複合物 」意謂包含IL-6受體子單元α (IL-6Rα)及介白素6信號轉導子糖蛋白130-亦稱為介白素6 受體子單元β (IL-6Rβ)-之蛋白質複合物。 「介白素 6 受體子單元 α (IL-6Rα) 多肽 」意謂與以NCBI寄存編號NP_000556或NP_852004提供之胺基酸序列具有至少約85%或大於85%之胺基酸一致性且具有IL-6受體生物活性之多肽或其片段。例示性IL-6Rα生物活性包括結合至IL-6、結合至糖蛋白130 (gp130)及調節細胞生長及分化。下文提供例示性IL-6R序列：「介白素 6 受體子單元 β (IL-6Rβ) 多肽 」意謂與以NCBI寄存編號NP_002175、NP_786943或NP_001177910提供之胺基酸序列具有至少約85%或大於85%之胺基酸一致性且具有IL-6受體生物活性之多肽或其片段。例示性IL-6Rβ生物活性包括結合至IL-6Rα、IL-6受體信號傳導活性，及調節細胞生長、分化、海帕西啶表現等。下文提供例示性IL-6Rβ序列： 「IL-6 拮抗劑 」意謂能夠降低IL-6之生物活性之藥劑。IL-6拮抗劑包括降低血清中IL-6多肽之含量之藥劑，包括降低IL-6多肽或核酸之表現之藥劑；降低IL-6結合至IL-6R之能力之藥劑；降低IL-6R之表現之藥劑；及當經IL-6結合時藉由IL-6R受體降低信號轉導之藥劑。在較佳實施例中，IL-6拮抗劑使IL-6生物活性降低至少約10%、20%、30%、50%、70%、80%、90%、95%或甚至100%。如下文部分5.9中進一步描述，IL-6拮抗劑包括IL-6結合多肽，諸如抗IL-6抗體及其抗原結合片段或衍生物；IL-6R結合多肽，諸如抗IL-6R抗體及其抗原結合片段或衍生物；及合成化學分子，諸如JAK1及JAK3抑制劑。 「IL-6 抗體 」或「抗 IL-6 抗體 」意謂特異性結合IL-6之抗體。抗IL-6抗體包括對IL-6具有特異性之單株及多株抗體及其抗原結合片段或衍生物。IL-6抗體在下文部分5.9.1中更詳細地描述。 「IL-6 介導之發炎病症 」意謂已知或懷疑IL-6促成疾病或其症狀中之任一者之病因之任何病症。 「紅血球生成素 (EPO) 」意謂與以NCBI寄存編號NP_000790提供之胺基酸序列具有至少約85%或大於85%之胺基酸一致性且具有EPO生物活性之多肽或其片段。例示性EPO生物活性包括結合至紅血球生成素受體及所產生之紅血球系前驅體細胞之增殖及最終分化及/或增加紅血球生成(紅血球產生)。下文提供例示性EPO胺基酸序列：「紅血球生成刺激劑 (ESA) 」意謂刺激紅血球生成之藥劑。ESA包括(但不限於)EPO；達貝泊汀(darbepoetin) (安然愛思普(Aranesp))；倍他依泊汀(epoetin beta) (新萊考蒙(NeoRecormon))；德耳塔依伯汀(epoetin delta) (對達因珀(Dynepo))；奧米伽依伯汀(epoetin omega) (Epomax)；澤塔依伯汀(epoetin zeta)。 「促紅血球形成因子 」意謂增加紅血球或其祖細胞(例如造血幹細胞)之生長或增殖及/或降低紅血球或其祖細胞之細胞死亡的藥劑。在各種實施例中，促紅血球形成因子包括紅血球生成刺激劑、HIF安定劑及補充鐵。 「C 反應蛋白 (CRP) 多肽 」意謂與以NCBI寄存編號NP_000558提供之胺基酸序列具有至少約85%或大於85%之胺基酸一致性且具有補體活化活性之多肽或其片段。CRP含量回應於發炎而增加。下文提供例示性CRP序列：「藥劑 」意謂適合於以療法投與之任何化合物或組合物，且明確地包括化學化合物；蛋白質，包括抗體或其抗原結合片段；肽；及核酸分子。 「個體 」意謂人類或非人類哺乳動物(包括(但不限於)牛、馬、犬、綿羊、貓及嚙齒動物，包括鼠類及家鼠屬)個體。「患者 」為人類個體。 如本文中所使用，術語「治療 (treat/treating/treatment) 」及其類似者係指降低或改善病症及/或與其相關之跡象或症狀，或減慢或停止其進程。應瞭解，雖然不排除，但治療病症或病狀並不需要完全消除該病症、病狀或與其相關之症狀。 「治療前 」意謂根據本文中所描述之方法在第一次投與IL-6拮抗劑之前。治療前不排除且常常包括先前投與IL-6拮抗劑以外之治療。 在本發明中，「包含 (comprises, comprising) 」、「含有 ( containing) 」、「具有 」、「包括 (includes, including) 」及其語言變化形式具有美國專利法律中賦予其之含義，允許明確敍述者以外其他組分之存在。 「生物樣本 」意謂來源於生物體(例如人類個體)之任何組織、細胞、體液或其他物質。在某些實施例中，生物樣本為血清或血液。 「血管收縮素轉化酶 (ACE) 抑制劑 」意謂抑制血管收縮素轉化酶將血管收縮素I轉化至血管收縮素II之生物功能的藥劑。ACE抑制劑包括(但不限於)喹那普利(quinapril)、培哚普利、雷米普利(ramipril)、卡托普利(captopril)、貝那普利(benazepril)、群多普利(trandolapril)、福辛普利(fosinopril)、賴諾普利(lisinopril)、莫西普利(moexipril)及依那普利(enalapril)。在各種實施例中，ACE抑制劑為培哚普利。 5.3 其他說明性慣例 除非另外規定，否則抗體恆定區殘基編號係根據Kabat中之EU索引。 本文中所提供之範圍應理解為範圍內所有值之簡寫，包括所述端點。舉例而言，1至50之範圍應理解為包括由以下組成之群的任何數值、數值之組合或子範圍：1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49及50。 除非上下文有特別規定或顯而易見，否則本文中所使用之術語「或」應理解為包括。除非上下文有特別規定或顯而易見，否則本文中所使用之術語「一」及「該」應理解為單數或複數。 除非上下文有特別規定或顯而易見，否則本文中所使用之術語「約」應理解為在此項技術中之正常容限範圍內，例如在平均值之2個標準偏差內。約可理解為在陳述值之10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%、0.1%、0.05%或0.01%內。除非另外自上下文顯而易見，否則本文中所提供之所有數值均由術語約修飾。 5.4 治療海帕西啶介導之病症之方法 在第一態樣中，提供治療海帕西啶介導之病症之方法。 該等方法包含向具有海帕西啶介導之病症之個體(通常人類患者)投與治療有效量之IL-6拮抗劑，其中已確定該個體具有TMPRSS6 rs855791主要對偶基因之至少一個複本。在第一系列之實施例中，先前已確定個體具有TMPRSS6 rs855791主要對偶基因之至少一個複本。在另一系列實施例中，該方法進一步包含確定個體具有TMPRSS6 rs855791主要對偶基因之至少一個複本之早前步驟。通常，該等方法肯定地排除治療對於TMPRSS6 rs855791次要對偶基因為同型接合之個體。通常，患者具有升高之治療前血清IL-6含量。 5.4.1 海帕西啶介導之病症 5.4.1.1 慢性疾病/慢性發炎貧血 在各種實施例中，藉由本文中所描述之方法治療的海帕西啶介導之病症為慢性疾病貧血，亦稱為慢性發炎貧血。 在各種實施例中，患者為男性且治療前血紅素(Hb)含量小於14 g/dl。在一些實施例中，男性患者之治療前Hb含量為13.0-13.9 g/dl、12.0-12.9 g/dl、11.0-11.9 g/dl、10.0-10.9 g/dl或小於10 g/dl。在各種實施例中，患者為女性且治療前Hb含量小於12 g/dl。在一些實施例中，女性患者之治療前Hb含量為11.0-11.9 g/dl、10.0-10.9 g/dl、9.0-9.9 g/dl、8.0-8.9 g/dl或小於8 g/dl。在一些此等實施例中，之前患者已用ESA治療。在一些實施例中，患者已藉由補鐵治療。在一些實施例中，患者已用血液或紅血球濃厚液之輸注來治療。 在各種實施例中，患者為男性且治療前血容比小於40%。在一些實施例中，男性患者之治療前血容比小於39%、小於38%、小於37%、小於36%或小於35%。在某些實施例中，男性患者之治療前血容比為39%、38%、37%、36%、35%、34%、33%、32%、31%或30%。在各種實施例中，患者為女性，且治療前血容比小於36%。在一些實施例中，女性患者之治療前血容比小於35%、34%、33%、32%、31%、30%、29%、28%、27%或26%。在某些實施例中，女性患者之治療前血容比為35%、34%、33%、32%、31%、30%、29%、28%、27%或26%。在一些此等實施例中，患者已用ESA治療。在一些實施例中，患者已藉由補鐵治療。在一些實施例中，患者已用血液或紅血球濃厚液之輸注來治療。 在一些實施例中，患者已用ESA治療且具有正常之治療前Hb含量及/或正常之治療前血容比。在某些實施例中，患者為男性且治療前血紅素(Hb)含量為至少14 g/dl，及/或治療前血容比為至少40%。在某些實施例中，患者為女性，且治療前Hb含量為至少12 g/dl及/或血容比為至少36%。在具體實施例中，ESA為EPO。在具體實施例中，ESA為達貝泊汀α (darbepoetin alfa)。 在一些實施例中，患者已藉由補鐵治療，且具有正常之治療前Hb含量及/或正常之治療前血容比。在某些實施例中，患者為男性且治療前血紅素(Hb)含量為至少14 g/dl，及/或治療前血容比為至少40%。在某些實施例中，患者為女性，且治療前Hb含量為至少12 g/dl及/或血容比為至少36%。 在一些實施例中，患者已用全血或紅血球濃厚液之輸注來治療，且具有正常之治療前Hb含量及/或正常之治療前血容比。在某些實施例中，患者為男性且治療前血紅素(Hb)含量為至少14 g/dl，及/或治療前血容比為至少40%。在某些實施例中，患者為女性，且治療前Hb含量為至少12 g/dl及/或血容比為至少36%。 在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使患者之Hb含量增加而高於治療前含量之時間期。在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使患者之血容比增加而高於治療前含量之時間期。在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使Hb含量及血容比兩者增加而高於治療前含量之時間期。 在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以在不降低患者之Hb含量的情況下使得患者之ESA劑量減少而低於治療前含量之時間期。在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以在不降低患者之血容比的情況下使得患者之ESA劑量減少而低於治療前含量之時間期。在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以在不降低患者之Hb含量及血容比的情況下使得患者之ESA劑量減少之時間期。 在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使得患者之ESA劑量相較於治療前ESA劑量減少至少10%之時間期。在某些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使得患者之ESA劑量相較於治療前ESA劑量減少至少20%、30%、40%或50%之時間期。在特定實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使得患者之ESA劑量相較於治療前ESA劑量減少至少60%或甚至至少75%之時間期。 在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以逆轉功能性鐵缺乏之時間期。 5.4.1.1.1 慢性腎病 在各種實施例中，慢性疾病為慢性腎病(CKD)。 在一些實施例中，患者患有KDOQI 1期慢性腎病。在某些實施例中，患者患有KDOQI 2期慢性腎病、KDOQI 3期慢性腎病、KDOQI 4期慢性腎病或KDOQI 5期慢性腎病。 在一些實施例中，患者患有心腎症候群(CRS)。在某些實施例中，患者患有4型CRS。 在一些實施例中，患者已用透析治療。 在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續相較於年齡匹配且疾病匹配之歷史群組足以降低心血管(CV)死亡率之時間期。 5.4.1.1.2 慢性發炎疾病 在各種實施例中，慢性疾病為慢性發炎疾病。 在一些實施例中，慢性發炎疾病為類風濕性關節炎(RA)。 在具體實施例中，患者之治療前DAS28得分大於5.1。在一些實施例中，患者之治療前DAS28得分為3.2至5.1。在一些實施例中，患者之治療前DAS28得分小於2.6。在各種實施例中，患者之治療前RA為重度活動性的。在一些實施例中，患者之治療前RA為中度活動性的。 在某些實施例中，患者已用甲胺喋呤治療。在一些實施例中，當啟動用IL-6拮抗劑進行之治療時，中斷甲胺喋呤。在一些實施例中，當啟動用IL-6拮抗劑進行之治療時，繼續用甲胺喋呤進行之治療。 在某些實施例中，患者已用抗TNFα劑治療。在特定實施例中，抗TNFα劑選自依那西普、阿達木單抗、英利昔單抗、賽妥珠單抗及戈利木單抗。在特定實施例中，當啟動用IL-6拮抗劑進行之治療時，中斷抗TNFα劑。 在某些實施例中，患者已用IL-1受體拮抗劑治療。在具體實施例中，IL-1受體拮抗劑為阿那白滯素(anakinra)。在特定實施例中，當啟動用IL-6拮抗劑進行之治療時，中斷IL-1受體拮抗劑。 在某些實施例中，患者已用阿巴西普(abatacept)治療。在特定實施例中，當啟動用IL-6拮抗劑進行之治療時，中斷阿巴西普。 在某些實施例中，患者已用IL-6拮抗劑治療，且方法進一步包含繼續向經最新確定具有TMPRSS6 rs855791主要對偶基因之至少一個複本之彼等患者僅投與IL-6拮抗劑。在具體實施例中，IL-6拮抗劑為托珠單抗。在具體實施例中，IL-6拮抗劑為托法替尼。 在各種實施例中，慢性發炎疾病選自由以下組成之群：幼年期特發性關節炎、僵直性脊椎炎、斑狀牛皮癬、牛皮癬性關節炎、發炎性腸病、克羅恩氏病及潰瘍性結腸炎。 5.4.1.1.3 癌症 在各種實施例中，慢性疾病為癌症。 在一些實施例中，癌症選自由以下組成之群：實體腫瘤、小細胞肺癌、非小細胞肺癌、血液癌、多發性骨髓瘤、白血病、慢性淋巴細胞白血病(CLL)、慢性骨髓性白血病(CML)、淋巴瘤及霍奇金氏淋巴瘤。 5.4.1.1.4 慢性感染 在各種實施例中，慢性疾病為慢性感染。 5.4.1.1.5 充血性心臟衰竭 在各種實施例中，慢性疾病為充血性心臟衰竭(CHF)。 5.4.1.2 鐵難治性缺鐵性貧血(IRIDA) 在各種實施例中，海帕西啶介導之病症為鐵難治性缺鐵性貧血(IRIDA)。 5.4.1.3 與海帕西啶產生之肝腺瘤相關之貧血 在各種實施例中，海帕西啶介導之病症為與海帕西啶產生之肝腺瘤相關之貧血。 5.4.1.4 急性冠狀動脈症候群 呈現於下文實例2、3及5中之資料表明在急性心肌梗塞之後，IL-6拮抗劑在降低心臟衰竭及死亡之風險中有效，且在增加心臟功能及降低纖維化中有效。因此，在各種實施例中，海帕西啶介導之病症急性冠狀動脈症候群。 在某些實施例中，患者在第一次投與IL-6拮抗劑之前的60天內已罹患心肌梗塞。在特定實施例中，患者在第一次投與IL-6拮抗劑之前的30天、14天、7天、48小時或24小時內已罹患心肌梗塞。 在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續相較於治療前程度足以改良心肌收縮性之時間期。在某些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續相較於治療前程度足以提高心臟射血分數之時間期。在某些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續相較於治療前程度足以降低心臟纖維化之時間期。5.4.1.5 卡斯爾曼氏病 在各種實施例中，海帕西啶介導之病症為卡斯爾曼氏病。 5.5 改良對海帕西啶介導之病症之治療的方法 在另一態樣中，提供藉由中斷為低效之療法而改良對海帕西啶介導之病症之治療的方法，從而在不喪失治療功效之情況下降低副作用且降低成本。該等方法包含向患有海帕西啶介導之病症之患者中斷IL-6拮抗劑之投與，其中已確定該患者針對TMPRSS6 rs855791次要對偶基因為同型接合的。在一系列實施例中，先前已確定患者針對TMPRSS6 rs855791次要對偶基因為同型接合的。在另一系列實施例中，方法進一步包含確定患者針對TMPRSS6 rs855791次要對偶基因為同型接合之早前步驟。在典型實施例中，患者具有升高之治療前血清IL-6含量。在各種實施例中，患者具有升高之治療前血清CRP含量。 在各種實施例中，患者具有選自上文部分5.4.1中所描述之彼等病症之海帕西啶介導之病症。在某些實施例中，患者患有慢性疾病貧血。 5.6 治療IL-6介導之發炎病症之方法 實例2、3及5中所呈現之資料表明在具有升高之治療前IL-6含量且具有TMPRSS6 主要對偶基因之至少一個複本、甚至不存在貧血之個體中，IL-6拮抗劑提供治療效益。因此，在另一態樣中，提供方法以治療無慢性發炎貧血之患者中的IL-6介導之發炎病症。 該等方法包含向患有IL-6介導之發炎病症之個體、通常人類患者投與治療有效量之IL-6拮抗劑，其中該患者不患有貧血，且其中已確定該個體具有TMPRSS6 rs855791主要對偶基因之至少一個複本。在第一系列之實施例中，先前已確定個體具有TMPRSS6 rs855791主要對偶基因之至少一個複本。在另一系列實施例中，方法進一步包含確定個體具有TMPRSS6 rs855791主要對偶基因之至少一個複本之早前步驟。通常，方法肯定地排除治療針對TMPRSS6 rs855791次要對偶基因為同型接合之個體。通常，患者具有升高之治療前血清IL-6含量。 在一些實施例中，IL-6介導之病症為類風濕性關節炎(RA)。 在具體實施例中，患者之治療前DAS28得分大於5.1。在一些實施例中，患者之治療前DAS28得分為3.2至5.1。在一些實施例中，患者之治療前DAS28得分小於2.6。在各種實施例中，患者之治療前RA為重度活動性的。在一些實施例中，患者之治療前RA為中度活動性的。 在某些實施例中，患者已用甲胺喋呤治療。在一些實施例中，當啟動用IL-6拮抗劑進行之治療時，中斷甲胺喋呤。在一些實施例中，當啟動用IL-6拮抗劑進行之治療時，繼續甲胺喋呤。 在某些實施例中，患者已用抗TNFα劑治療。在特定實施例中，抗TNFα劑選自依那西普、阿達木單抗、英利昔單抗、賽妥珠單抗及戈利木單抗。在特定實施例中，當啟動用IL-6拮抗劑進行之治療時，中斷抗TNFα劑。 在某些實施例中，患者已用IL-1受體拮抗劑治療。在具體實施例中，IL-1受體拮抗劑為阿那白滯素。在特定實施例中，當啟動用IL-6拮抗劑進行之治療時，中斷IL-1受體拮抗劑。 在某些實施例中，患者已用阿巴西普治療。在特定實施例中，當啟動用IL-6拮抗劑進行之治療時，中斷阿巴西普。 在各種實施例中，IL-6介導之病症選自由以下組成之群：幼年期特發性關節炎、僵直性脊椎炎、斑狀牛皮癬、牛皮癬性關節炎、發炎性腸病、克羅恩氏病及潰瘍性結腸炎。 5.7 治療前血清IL-6及CRP含量 在本文中所描述之方法之典型實施例中，患者具有升高之治療前血清IL-6含量。 在一些實施例中，患者之治療前血清IL-6含量大於2.5 pg/ml。在各種實施例中，患者之治療前血清IL-6含量大於5 pg/ml、大於7.5 pg/ml、大於10 pg/ml、大於12.5 pg/ml或大於15 pg/ml。 在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使患者之血清IL-6含量降低而低於治療前含量之時間期。在某些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使患者之血清IL-6含量相較於治療前含量降低至少10%、20%、30%、40%或50%之時間期。 在各種實施例中，患者具有升高之治療前C反應蛋白(CRP)含量。在一些實施例中，患者之治療前CRP含量大於2 mg/ml、2.5 mg/ml、3 mg/ml、3.5 mg/ml、4 mg/ml、4.5 mg/ml或5 mg/ml。在一些實施例中，患者之治療前CRP含量大於7.5 mg/ml、10 mg/ml、12.5 mg/ml或15 mg/ml。 在一些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使患者之CRP含量降低而低於治療前含量之時間期。在某些實施例中，按時程投與一劑IL-6拮抗劑劑量，且持續足以使患者之CRP含量相較於治療前含量降低至少10%、20%、30%、40%或50%之時間期。 5.8TMPRSS6 rs855791基因分型 本文中所描述之方法包含向已確定具有TMPRSS6 rs855791主要對偶基因之至少一個複本之個體投與治療有效量之IL-6拮抗劑。較佳地，鑑別對應於相關基因之兩個對偶基因，因此允許鑑別且區分以下患者：針對TMPRSS6 rs855791主要對偶基因為同型接合的，針對主要及次要TMPRSS6 rs855791對偶基因為異型接合的，及針對TMPRSS6 rs855791次要對偶基因為同型接合的。 使用標準技術確定SNP rs855791 (2321G→A)在TMPRSS6 基因中之缺乏(主要對偶基因)或存在(次要對偶基因)。 通常，PCR用以擴增獲自患者之生物樣本。 在一些實施例中，同時使用即時PCR(RT-PCR)在擴增下偵測多形現象之缺乏或存在。在某些實施例中，RT-PCR分析採用5'核酸酶(TaqMan®探針)、分子信標及/或FRET雜交探針。綜述於 Espy等人,Clin. Microbiol. Rev . 2006年1月; 19(1): 165-256中，其以全文引用之方式併入本文中。在典型實施例中，使用商業上可獲得之分析。在所選實施例中，商業上可獲得之分析選自由以下組成之群：TaqMan™ SNP基因分型分析(ThermoFisher)；PCR SNP基因分型分析(Qiagen)；Novallele 基因分型分析(Canon)；及SNP Type™分析(以前SNPtype) (Fluidigm)。 在一些實施例中，在擴增後使用用對SNP rs855791具有特異性之探針之雜交、限制性核酸內切酶消化、核酸定序、引子延伸、微陣列或基因晶片分析、質譜分析及/或DNA酶保護分析，來偵測多形現象之缺乏或存在。在一些實施例中，對偶基因變異體藉由定序判讀。在某些實施例中，使用桑格定序(Sanger sequencing)。在某些實施例中，使用各種下一代定序技術中之一者，包括例如選自由以下組成之群的定序技術：微陣列定序、Solexa定序(Illumina)、離子急流(Life Technologies)、SOliD (Applied Biosystems)、焦磷酸定序、單分子即時定序(Pacific Bio)、奈米孔定序及隧道電流定序。 5.9 IL-6拮抗劑 用於本文中所描述之方法之IL-6拮抗劑能夠降低IL-6之生物活性。 5.9.1 抗IL-6抗體 在各種實施例中，IL-6拮抗劑為抗IL-6抗體或其抗原結合片段或衍生物。 在一些實施例中，IL-6拮抗劑為全長抗IL-6單株抗體。在特定實施例中，全長單株抗體為IgG抗體。在某些實施例中，全長單株抗體為IgG1、IgG2、IgG3或IgG4抗體。在一些實施例中，IL-6拮抗劑為多株組合物，其包含全長抗IL-6抗體之複數種物質，該複數種物中之每一者具有獨特CDR。在一些實施例中，IL-6拮抗劑為選自Fab、Fab'及F(ab')2片段之抗體片段。在一些實施例中，IL-6拮抗劑為scFv、經二硫鍵連接之Fv (dsFv)或單域抗體，諸如源於駱駝之VHH單域奈米抗體。在一些實施例中，IL-6拮抗劑為包含IL-6抗原結合片段之免疫結合物或融合物。在一些實施例中，抗體為雙特異性或多特異性的，其中抗原結合部分中之至少一者具有針對IL-6之特異性。 在一些實施例中，抗體為完全人類的。在一些實施例中，抗體為人類化的。在一些實施例中，抗體為嵌合的且具有非人類V區及人類C區域。在一些實施例中，抗體為鼠的。 在典型實施例中，抗IL-6抗體對人類IL-6之結合性具有小於100 nM之KD 。在一些實施例中，抗IL-6抗體對人類IL-6之結合性具有小於75 nM、50 nM、25 nM、20 nM、15 nM或10 nM之KD 。在特定實施例中，抗IL-6抗體對人類IL-6之結合性具有小於5 nM、4 nM、3 nM或2 nM之KD 。在所選擇實施例中，抗IL-6抗體對人類IL-6之結合性具有小於1 nM、750 pM或500 pM之KD 。在具體實施例中，抗IL-6抗體對人類IL-6之結合性具有不大於500 pM、400 pM、300 pM、200 pM或100 pM之KD 。 在典型實施例中，抗IL-6抗體中和IL-6之生物活性。在一些實施例中，中和抗體阻止IL-6結合至IL-6受體。 在典型實施例中，抗IL-6抗體在靜脈內投與後具有至少7天之消除半衰期。在某些實施例中，抗IL-6抗體之消除半衰期為至少14天、至少21天或至少30天。 在一些實施例中，相較於未經取代之人類IgG恆定域，抗IL-6抗體具有具至少一個胺基酸取代(延長血清半衰期)之人類IgG恆定區。 在某些實施例中，IgG恆定域包含在殘基252、254及256處之取代，其中胺基酸殘基252處之胺基酸取代為經酪胺酸取代，胺基酸殘基254處之胺基酸取代為經蘇胺酸取代，且胺基酸殘基256處之胺基酸取代為經麩胺酸取代(「YTE」)。參見美國專利第7,083,784號，其以全文引用之方式併入本文中。在某些延長半衰期實施例中，IgG恆定域包含選自以下的取代：T250Q/M428L (Hinton等人,J. Immunology 176:346-356 (2006))；N434A (Yeung等人,J. Immunology 182:7663-7671 (2009))；或T307A/E380A/N434A (Petkova等人,International Immunology , 18: 1759-1769 (2006))。 在一些實施例中，抗IL-6抗體之消除半衰期藉由利用人類血清白蛋白之FcRN結合特性來增加。在某些實施例中，抗體結合至白蛋白(Smith等人,Bioconjug. Chem ., 12: 750-756 (2001))。在一些實施例中，抗IL-6抗體融合至細菌白蛋白結合域(Stork等人,Prot. Eng. Design Science 20: 569-76 (2007))。在一些實施例中，抗IL-6抗體融合至白蛋白結合肽(Nguygen等人,Prot Eng Design Sel 19: 291-297 (2006))。在一些實施例中，抗IL抗體為雙特異性，其中一種特異性針對IL-6，且一種特異性針對人類血清白蛋白(Ablynx，WO 2006/122825(雙特異性奈米抗體))。 在一些實施例中，抗IL-6抗體之消除半衰期藉由以下增加：PEG化(Melmed等人,Nature Reviews Drug Discovery 7: 641-642 (2008))；HPMA共聚物結合(Lu等人,Nature Biotechnology 17: 1101-1104 (1999))；聚葡萄糖結合(Nuclear Medicine Communications , 16: 362-369 (1995))；與高胺基酸聚合物(HAP；HAP化)之結合(Schlapschy等人,Prot Eng Design Sel 20: 273-284 (2007))；或聚唾液酸化(Constantinou等人,Bioconjug. Chem . 20: 924-931 (2009))。 5.9.1.1.1 MED5117及衍生物 在某些實施例中，抗IL-6抗體或其抗原結合部分包含MEDI5117之所有六個CDR。在特定實施例中，抗體或其抗原結合部分包含MEDI5117重鏈V區及輕鏈V區。在具體實施例中，抗體為全長MEDI5117抗體。MEDI5117抗體描述於揭示內容以全文引用之方式併入本文中之WO 2010/088444及US 2012/0034212中。MEDI5117抗體具有以下CDR及重鏈及輕鏈序列： MEDI5117 VH CDR1MEDI5117 VH CDR2MEDI5117 VH CDR3MEDI5117 VL CDR1MEDI5117 VL CDR2MEDI5117 VL CDR3MEDI5117重鏈MEDI5117輕鏈在各種實施例中，抗IL-6抗體為MED5117之衍生物。 在一些實施例中，MED5117衍生物在MED5117重鏈及/或輕鏈V區中包括一或多個胺基酸取代。 在某些實施例中，相對於MEDI5117抗IL-6抗體之最初VH 及/或VL ，衍生物包含少於25個胺基酸取代、少於20個胺基酸取代、少於15個胺基酸取代、少於10個胺基酸取代、少於5個胺基酸取代、少於4個胺基酸取代、少於3個胺基酸取代、少於2個胺基酸取代或1個胺基酸取代，同時保留針對人類IL-6之特異性。 在某些實施例中，MED5117衍生物包含與MEDI5117之VH及VL域之胺基酸序列至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%或至少99%一致之胺基酸序列。使用BLAST演算法使用預設參數確定序列一致性百分比。 在某些實施例中，MED5117衍生物包含以下胺基酸序列：其中CDR包含與MEDI5117之各別CDR之胺基酸序列至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%或至少99%一致之胺基酸序列。使用BLAST演算法使用預設參數確定序列一致性百分比。 在某些實施例中，VH 及/或VL CDR衍生物在一或多個經預測非必需胺基酸殘基(亦即，對抗體特異性結合至人類IL-6不至關重要之胺基酸殘基)處包含保守胺基酸取代。 5.9.1.1.2 其他抗IL-6抗體 在各種實施例中，抗IL-6抗體包含來自選自由以下組成之群的抗體之六個CDR：司妥昔單抗、格里林祖單抗、思魯庫單抗、克拉雜奇單抗、奧諾奇單抗、艾思莫單抗、VX30 (VOP-R003；Vaccinex)、EB-007 (EBI-029；Eleven Bio)、ARGX-109 (ArGEN-X)、FM101 (Femta Pharmaceuticals，Lonza)及ALD518/BMS-945429 (Alder Biopharmaceuticals，Bristol-Myers Squibb)。在某些實施例中，抗IL-6抗體包含來自選自由以下組成之群的抗體之重鏈V區及輕鏈V區：司妥昔單抗、格里林祖單抗、思魯庫單抗、克拉雜奇單抗、奧諾奇單抗、VX30 (VOP-R003；Vaccinex)、EB-007 (EBI-029；Eleven Bio)、ARGX-109 (ArGEN-X)、FM101 (Femta Pharmaceuticals，Lonza)及ALD518/BMS-945429 (Alder Biopharmaceuticals，Bristol-Myers Squibb)。在特定實施例中，抗IL-6抗體為選自由以下組成之群的抗體：司妥昔單抗、格里林祖單抗、思魯庫單抗、克拉雜奇單抗、奧諾奇單抗、VX30 (VOP-R003；Vaccinex)、EB-007 (EBI-029；Eleven Bio)、ARGX-109 (ArGEN-X)、FM101 (Femta Pharmaceuticals，Lonza)及ALD518/BMS-945429 (Alder Biopharmaceuticals，Bristol-Myers Squibb)。 在一些實施例中，抗IL-6抗體包含來自選自以下各者中所描述之彼等抗體之抗體的六個CDR：US 2016/0168243、US 2016/0130340、US 2015/0337036、US 2015/0203574、US 2015/0140011、US 2015/0125468、US 2014/0302058、US 2014/0141013、US 2013/0280266、US 2013/0017575、US 2010/0215654、US 2008/0075726、美國專利第5,856,135號、US 2006/0240012、US 2006/0257407或美國專利第7291721號，其揭示內容以全文引用之方式併入本文中。 5.9.2 抗IL-6受體抗體 在各種實施例中，IL-6拮抗劑為抗IL-6受體抗體或其抗原結合片段或衍生物。 在一些實施例中，IL-6拮抗劑為全長抗IL-6受體單株抗體。在特定實施例中，全長單株抗體為IgG抗體。在某些實施例中，全長單株抗體為IgG1、IgG2、IgG3或IgG4抗體。在一些實施例中，IL-6拮抗劑為多株組合物，其包含全長抗IL-6受體抗體之複數種物質，該複數種物中之每一者具有獨特CDR。在一些實施例中，IL-6拮抗劑為選自Fab及Fab'片段之抗體片段。在一些實施例中，IL-6拮抗劑為scFv、單域抗體，包括源於駱駝之VHH單域奈米抗體。在一些實施例中，抗體為雙特異性或多特異性的，其中抗原結合部分中之至少一者具有針對IL-6R之特異性。 在一些實施例中，抗體為完全人類的。在一些實施例中，抗體為人類化的。在一些實施例中，抗體為嵌合的且具有非人類V區及人類C區域。在一些實施例中，抗體為鼠的。 在典型實施例中，抗IL-6受體抗體對人類IL-6R之結合性具有小於100 nM之KD 。在一些實施例中，抗IL-6R抗體對人類IL-6R之結合性具有小於75 nM、50 nM、25 nM、20 nM、15 nM或10 nM之KD 。在特定實施例中，抗IL-6受體抗體對人類IL-6R之結合性具有小於5 nM、4 nM、3 nM或2 nM之KD 。在所選擇實施例中，抗IL-6受體抗體對人類IL-6R之結合性具有小於1 nM、750 pM或500 pM之KD 。在具體實施例中，抗IL-6受體抗體對人類IL-6R之結合性具有不大於500 pM、400 pM、300 pM、200 pM或100 pM之KD 。 在典型實施例中，抗IL-6R降低IL-6之生物活性。 在典型實施例中，抗IL-6R抗體在靜脈內投與後具有至少7天之消除半衰期。在某些實施例中，抗IL-6R抗體之消除半衰期為至少14天、至少21天或至少30天。 在一些實施例中，相較於未經取代之人類IgG恆定域，抗IL-6R抗體具有具至少一個胺基酸取代(延長血清半衰期)之人類IgG恆定區。 在某些實施例中，IgG恆定域包含在殘基252、254及256處之取代，其中胺基酸殘基252處之胺基酸取代為經酪胺酸取代，胺基酸殘基254處之胺基酸取代為經蘇胺酸取代，且胺基酸殘基256處之胺基酸取代為經麩胺酸取代(「YTE」)。參見美國專利第7,083,784號，其以全文引用之方式併入本文中。在某些延長半衰期實施例中，IgG恆定域包含選自以下的取代：T250Q/M428L (Hinton等人, J. Immunology 176:346-356 (2006))；N434A (Yeung等人, J. Immunology 182:7663-7671 (2009))；或T307A/E380A/N434A (Petkova等人, International Immunology, 18: 1759-1769 (2006))。 在一些實施例中，抗IL-6R抗體之消除半衰期藉由利用人類血清白蛋白之FcRN結合特性來增加。在某些實施例中，抗體結合至白蛋白(Smith等人, Bioconjug. Chem., 12: 750-756 (2001))。在一些實施例中，抗IL-6R抗體融合至細菌白蛋白結合域(Stork等人, Prot. Eng. Design Science 20: 569-76 (2007))。在一些實施例中，抗IL-6抗體融合至白蛋白結合肽(Nguygen等人, Prot Eng Design Sel 19: 291-297 (2006))。在一些實施例中，抗IL抗體為雙特異性的，其中一種特異性針對IL-6R，且一種特異性針對人類血清白蛋白(Ablynx，WO 2006/122825(雙特異性奈米抗體))。 在一些實施例中，抗IL-6R抗體之消除半衰期藉由以下增加：PEG化(Melmed等人, Nature Reviews Drug Discovery 7: 641-642 (2008))；HPMA共聚物結合(Lu等人, Nature Biotechnology 17: 1101-1104 (1999))；聚葡萄糖結合(Nuclear Medicine Communications, 16: 362-369 (1995))；與高胺基酸聚合物(HAP；HAP化)之結合(Schlapschy等人, Prot Eng Design Sel 20: 273-284 (2007))；或聚唾液酸化(Constantinou等人, Bioconjug. Chem. 20: 924-931 (2009))。 在某些實施例中，抗IL-6R抗體或其抗原結合部分包含托珠單抗之所有六個CDR。在特定實施例中，抗體或其抗原結合部分包含托珠單抗重鏈V區及輕鏈V區。在具體實施例中，抗體為全長托珠單抗抗體。 在某些實施例中，抗IL-6R抗體或其抗原結合部分包含莎麗路單抗(sarilumab)之所有六個CDR。在特定實施例中，抗體或其抗原結合部分包含莎麗路單抗重鏈V區及輕鏈V區。在具體實施例中，抗體為全長莎麗路單抗抗體。 在某些實施例中，抗IL-6R抗體或其抗原結合部分包含以下之所有六個CDR：VX30 (Vaccinex)、ARGX-109 (arGEN-X)、FM101 (Formatech)、SA237 (Roche)、NI-1201 (NovImmune)或US 2012/0225060中所描述之抗體。 在某些實施例中，抗IL-6R抗體或其抗原結合部分為單域抗體。在特定實施例中，單域抗體為駱駝VHH單域抗體。在具體實施例中，抗體為夫巴利珠單抗(ALX-0061) (Ablynx NV)。 5.9.3 抗IL-6:IL-6R複合物抗體 在各種實施例中，IL-6拮抗劑為對IL-6與IL-6R之複合物具有特異性之抗體。在某些實施例中，抗體具有選自US 2011/0002936中所描述之彼等抗體之抗體的六個CDR，該US 2011/0002936以全文引用之方式併入本文中。 5.9.4 JAK及STAT抑制劑 已知IL-6經由JAK-STAT路徑傳信。 在各種實施例中，IL-6拮抗劑為JAK信號傳導路徑之抑制劑。在一些實施例中，JAK抑制劑為JAK1特異性抑制劑。在一些實施例中，JAK抑制劑為JAK3特異性抑制劑。在一些實施例中，JAK抑制劑為泛JAK抑制劑。 在某些實施例中，JAK抑制劑選自由以下組成之群：托法替尼(Xeljanz)、得森替尼、盧佐替尼、尤帕達替尼、巴瑞替尼、斐哥替尼、來妥替尼、帕瑞替尼、皮非替尼、INCB-039110、ABT-494、INCB-047986及AC-410。 在各種實施例中，IL-6拮抗劑為STAT3抑制劑。在一具體實施例中，抑制劑為AZD9150 (AstraZeneca，Isis Pharmaceuticals)、STAT3反義分子。 5.9.5 額外IL-6拮抗劑 在各種實施例中，IL-6拮抗劑為拮抗劑肽。 在某些實施例中，IL-6拮抗劑為C326 (Avidia之IL-6抑制劑，亦稱為AMG220)或FE301，一種IL-6之重組蛋白抑制劑(Ferring International Center S.A.，Conaris Research Institute AG)。在一些實施例中，抗IL-6拮抗劑包含可溶性gp130、FE301 (Conaris/Ferring)。 5.10 給藥方案 5.10.1 抗體、抗原結合片段、肽 在典型實施例中，抗體、抗原結合片段及肽IL-6拮抗劑非經腸投與。 在一些非經腸實施例中，IL-6拮抗劑經靜脈內投與。在某些靜脈內實施例中，IL-6拮抗劑以藥團形式投與。在某些靜脈內實施例中，IL-6拮抗劑以輸液形式投與。在某些靜脈內實施例中，IL-6拮抗劑以藥團形式、隨後以輸液形式投與。在一些非經腸實施例中，IL-6拮抗劑經皮下投與。 在各種實施例中，抗體、抗原結合片段或肽IL-6拮抗劑以不依賴患者體重或表面積之劑量(均一劑量)投與。 在一些實施例中，靜脈內均一劑量為1 mg、2 mg、3 mg、4 mg、5 mg、6 mg、7 mg、8 mg、9 mg或10 mg。在一些實施例中，靜脈內均一劑量為11 mg、12 mg、13 mg、14 mg、15 mg、16 mg、17 mg、18 mg、19 mg或20 mg。在一些實施例中，靜脈內均一劑量為25 mg、30 mg、40 mg或50 mg。在一些實施例中，靜脈內均一劑量為60 mg、70 mg、80 mg、90 mg或100 mg。在一些實施例中，靜脈內均一劑量為1 - 10mg、10 - 15 mg、15 - 20 mg、20 - 30 mg、30 - 40 mg或40 - 50 mg。在一些實施例中，靜脈內均一劑量為1 - 40 mg或50 - 100 mg。 在一些實施例中，皮下均一劑量為10 mg、20 mg、30 mg、40 mg、50 mg、60 mg、70 mg、80 mg、90 mg或100 mg。在一些實施例中，皮下均一劑量為110 mg、120 mg、130 mg、140 mg、150 mg、160 mg、170 mg、180 mg、190 mg或200 mg。在一些實施例中，皮下均一劑量為210 mg、220 mg、230 mg、240 mg或250 mg。在一些實施例中，皮下均一劑量為10 - 100 mg、100 - 200 mg或200 - 250 mg。在一些實施例中，皮下均一劑量為10 - 20 mg、20 - 30 mg、30 - 40 mg、40 - 50 mg、50 - 60 mg、60 - 70 mg、70 - 80 mg、80 - 90 mg或90 - 100 mg。在一些實施例中，皮下均一劑量為100 - 125 mg、125 - 150 mg、150 -175 mg、175 - 200 mg或200 - 250 mg。 在各種實施例中，抗體、抗原結合片段或肽IL-6拮抗劑以基於患者體重之劑量投與。 在一些實施例中，拮抗劑以0.1 mg/kg、0.2 mg/kg、0.3 mg/kg、0.4 mg/kg、0.5 mg/kg、0.6 mg/kg、0.7 mg/kg、0.8 mg/kg、0.9 mg/kg或1.0 mg/kg之靜脈內劑量投與。在一些實施例中，拮抗劑以1.5 mg/kg、2 mg/kg、2.5 mg/kg、3 mg/kg、3.5 mg/kg、4 mg/kg、4.5 mg/kg或5 mg/kg之劑量投與。 在一些實施例中，皮下之基於體重之劑量為0.1 mg/kg、0.2 mg/kg、0.3 mg/kg、0.4 mg/kg、0.5 mg/kg、0.6 mg/kg、0.7 mg/kg、0.8 mg/kg、0.9 mg/kg或1.0 mg/kg。在一些實施例中，拮抗劑以1.5 mg/kg、2 mg/kg、2.5 mg/kg、3 mg/kg、3.5 mg/kg、4 mg/kg、4.5 mg/kg或5 mg/kg之劑量投與。 在各種靜脈內實施例中，IL-6拮抗劑每7天投與一次、每14天投與一次、每21天投與一次、每28天投與一次或一月投與一次。在各種皮下實施例中，IL-6拮抗劑每14天投與一次、每28天投與一次、一月投與一次、每兩個月(每隔一個月)投與一次或每三個月投與一次。 在某些較佳實施例中，IL-6拮抗劑為MEDI5117抗體。在各種實施例中，MEDI5117以1 -30 mg之均一劑量每週一次IV投與。在某些實施例中，MEDI5117抗體以1、2、3、4、5、7.5、10、15、20、25或30 mg之均一劑量每週一次IV投與。在一些實施例中，MEDI5117抗體以25 - 250 mg之均一劑量每月一次至每三個月一次s.c.投與。在特定實施例中，MEDI5117以30 mg、45 mg、60 mg、75 mg、100 mg、120 mg、125 mg、150 mg、175 mg、200 mg、225 mg、240 mg或250 mg之劑量每月一次、每兩個月一次或每3個月一次s.c.投與。 在一些實施例中，IL-6拮抗劑為托珠單抗。在各種實施例中，針對≥100 kg之患者，托珠單抗以162 mg之起始劑量每週一次s.c.投與。在一些實施例中，基於臨床反應，托珠單抗以4 mg/kg劑量每4週一次、隨後升高至8 mg/kg每4週一次靜脈內投與。 5.10.2 JAK及STAT抑制劑 在典型實施例中，小分子JAK抑制劑及STAT抑制劑經口投與。 在各種實施例中，抑制劑以1 - 10 mg、10 - 20 mg、20 - 30 mg、30 - 40 mg或40 - 50 mg之口服劑量一天一次或兩次投與。在一些實施例中，抑制劑以50 - 60 mg、60 - 70 mg、70 - 80 mg、80 - 90 mg或90 - 100 mg之劑量一天一次或兩次投與。在一些實施例中，抑制劑以5、10、15、20、25、30、35、40、45或50 mg之劑量一天一次或兩次PO投與。在一些實施例中，抑制劑以75 mg劑量PO QD或BID投與，以100 mg劑量PO QD或BID投與。 在某些實施例中，JAK抑制劑為托法替尼，且以5 mg劑量PO BID投與，或以11 mg劑量PO QD投與。 在某些實施例中，JAK抑制劑為得森替尼，且以25 mg、50 mg、100 mg或150 mg之劑量PO BID投與。 在某些實施例中，抑制劑為盧佐替尼，且以25 mg劑量PO BID投與，以20 mg劑量PO BID投與，以15 mg劑量PO BID投與，以10 mg劑量PO BID投與或以5 mg劑量PO BID投與。 5.11 其他治療劑 在本文中所描述之方法之各種實施例中，方法進一步包含投與除IL-6拮抗劑之外之治療劑，其中第二治療劑亦能夠降低海帕西啶表現。 在一些實施例中，第二治療劑為BMP拮抗劑。在某些實施例中，BMP拮抗劑為抗BMP6抗體。在特定實施例中，抗BMP6抗體具有US 2016/0176956或US 2016/0159896中所描述之抗體之六個CDR，該等案之揭示內容以全文引用之方式併入本文中。 在某些實施例中，第二治療劑為鐵調素調節蛋白拮抗劑。在特定實施例中，鐵調素調節蛋白拮抗劑為抗鐵調素調節蛋白抗體。在具體實施例中，抗鐵調素調節蛋白抗體具有Kovac等人,Haematologica (2016) doi:10.3324/ haematol.2015.140772[印刷之前的電子版]中所揭示之抗體的六個CDR。 在某些實施例中，第二治療劑為海帕西啶拮抗劑。在特定實施例中，海帕西啶拮抗劑為抗海帕西啶抗體。在具體實施例中，抗體具有US 2016/0017032中所描述之抗體之六個CDR，該案之揭示內容以全文引用之方式併入本文中。 5.12 套組 在另一態樣中，提供套組。 在典型實施例中，套組提供試劑以自獲自患者之生物樣本確定患者之TMPRSS6 SNP rs855791位置處之基因型。 5.13 其他態樣及實施例 5.13.1 治療慢性腎病或心血管疾病中之發炎之方法 在其他態樣及實施例中，提供用於用IL-6拮抗劑表徵且治療慢性腎病或心血管疾病中之發炎之組合物及方法，以及用於表徵患者對治療之反應之方法。 此等態樣及實施例至少部分基於以下發現：具有在核苷酸位置2321處包含G或C之TMPRSS6 的一或多個對偶基因(編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽)的慢性腎病患者及心血管疾病患者之發炎使得此等患者具有較高死亡風險，且此類個體可用IL-6拮抗劑治療以降低此風險。如下文更詳細報導，將慢性腎病患者基因分型，分析IL-6及CRP之血清含量，且將此等診斷資料與所投與之EPO給藥及死亡風險相比。具有在核苷酸位置2321處包含G或C之TMPRSS6 之一或多個對偶基因(編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽)，及升高之IL-6及/或CRP含量的患者需要更高之EPO劑量來治療，且具有較高死亡率。已顯示在鑑別患有缺鐵性貧血之患者中，此位置處之核苷酸很重要(參見Finberg等人,Nat. Genet. 2008; 40(5): 569-571，將其教示且關於序列、變異體、命名法等之全部內容特此以全文引用之方式併入)。此等資料強烈地支持基於TMPRSS6 基因型鑑別患者子集，其需要較高的EPO劑量及/或具有較高死亡風險，且在存在或不存在用於治療貧血(例如與慢性腎病相關)之標準療法下將可能對IL-6抑制起反應。藉由抑制發炎，可減少EPO給藥，從而避免EPO之不利副作用(例如心血管風險)。 此等態樣及實施例進一步基於以下發現：具有在核苷酸位置2321處包含G或C之TMPRSS6 之一或多個對偶基因(編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽)的患者處於與心肌梗塞或心血管疾病相關之更高的死亡風險下。此等患者將亦可能受益於IL-6抑制，其將降低發炎及增加之風險。 因此，提供以下治療方法：藉由抑制例如在藉由SNP rs855791處之TMPRSS6 基因分型而選擇之患者中之IL-6生物活性，藉由阻斷IL-6或其受體(gp80)彼此結合，或阻斷其信號傳導或表現(例如藉由抗IL-6抗體或藉由抗IL-6R抗體或JAK1/STAT3抑制)，來治療與心血管疾病或慢性腎病(包括慢性腎病貧血)相關之發炎，及/或降低與此類病狀相關之死亡風險。在一個實施例中，慢性腎病之治療在存在或不存在用於貧血之標準治療以及以下方法下進行：例如藉由對SNP rs855791處之TMPRSS6 基因分型且偵測發炎標記物之含量(例如增加之IL-6及/或CRP血清含量)，來表徵罹患慢性腎病之患者對用於貧血之治療的反應。 提供藉由投與抑制IL-6生物活性或表現之藥劑來治療心血管疾病或慢性腎病貧血及/或降低與此類患者之慢性發炎相關之死亡的方法。 在一些態樣及實施例中，提供用於治療促進患有慢性腎病或心血管疾病之個體之死亡的慢性發炎，且用於表徵患者對此類療法之反應之組合物及方法。在特定實施例中，提供用於表徵且治療慢性發炎貧血及死亡(例如在慢性腎病中)以及用於表徵患者對用於貧血之治療(例如投與紅血球生成素或紅血球生成刺激劑)之反應的方法。在一個態樣中，提供治療經選擇個體之慢性發炎之方法，方法包含向個體投與IL-6拮抗劑，其中針對治療，個體藉由具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因經選擇。 在另一態樣中，提供用於治療患有心血管疾病或慢性腎病之經選擇個體之發炎或慢性發炎的方法，方法涉及向個體投與IL-6拮抗劑(例如抗IL-6抗體)，其中針對治療，個體藉由具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因經選擇。在一個實施例中，方法降低個體之死亡風險。在一個實施例中，個體具有心肌梗塞或心臟衰竭之病史。 在另一態樣中，提供降低患有心血管疾病或腎病之經選擇個體之發炎及死亡風險的方法，方法包含向個體投與IL-6拮抗劑(例如抗IL-6抗體)，其中個體經選擇為具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因，且相對於參照患有增加之發炎。在一個實施例中，個體具有心肌梗塞或心臟衰竭之病史。 在另一態樣中，提供用於降低患有慢性腎病或心臟衰竭之個體之死亡風險的方法，方法包含向個體投與IL-6拮抗劑，其中個體經鑑別為具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因，且相對於參照患有增加之發炎。 在另一態樣中，提供治療個體之貧血之方法，方法涉及向個體投與單獨或與用於貧血之療法組合之IL-6拮抗劑，其中個體經鑑別為具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽(亦稱為間質蛋白酶-2；MT2)之一或多個對偶基因(例如在TMPRSS6 核酸分子之核苷酸位置2321處具有G或C)，且相對於參照患有增加之發炎。 在另一態樣中，提供治療患有增加之發炎的個體之貧血之方法，方法涉及以有效地中和個體之發炎之量投與單獨或與促紅血球形成因子組合之IL-6拮抗劑(例如IL-6抗體),該個體具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因(例如在TMPRSS6 核酸分子之核苷酸位置2321處具有G或C)。 在再一態樣中，提供在鑑別為有需要之個體中增強對EPO之反應的方法，方法包含以有效地中和個體之發炎之量投與IL-6拮抗劑(例如IL-6抗體)，從而減少EPO劑量，該個體具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因(例如在TMPRSS6 核酸分子之核苷酸位置2321處具有G或C)。 在另一態樣中，提供降低患有增加之發炎的個體之死亡之方法，方法涉及以有效地中和個體之發炎之量投與IL-6拮抗劑，該個體具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因(例如在TMPRSS6 核酸分子之核苷酸位置2321處具有G或C)。 在又一態樣中，提供為鑑別為有需要之個體選擇療法之方法，方法涉及：表徵以下個體：具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因(例如在TMPRSS6 核酸分子之核苷酸位置2321處具有G或C)；及偵測一或多種發炎標記物IL-6或CRP之含量，其中表徵指示IL-6拮抗劑應單獨或與用於貧血之療法組合投與。 在又一態樣中，提供用於增加鑑別為有需要之個體中之紅血球或其祖細胞(例如造血幹細胞、前紅血球母細胞、紅血球母細胞或網狀紅血球)的增殖或存活之方法，方法包含向個體投與IL-6拮抗劑及促紅血球形成因子，其中個體經鑑別為具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因(例如在TMPRSS6 核酸分子之核苷酸位置2321處具有G或C)，且相對於參照患有增加之發炎。 在本文中所敍述態樣中之任一者之各種實施例中，個體患有或經鑑別為患有貧血，包括癌症貧血、慢性自體免疫疾病中之貧血、慢性發炎疾病中之貧血、心血管疾病中之貧血、代謝症候群中之貧血及其類似貧血。在本文中所敍述態樣中之任一者之各種實施例中，個體患有或經鑑別為患有慢性腎病。在本文中所敍述態樣中之任一者之各種實施例中，個體患有或經鑑別為患有發炎。在本文中所敍述態樣中之任一者之各種實施例中，個體具有或經鑑別為具有增加之與慢性發炎、慢性腎病或心血管疾病相關之死亡風險。在本文中所敍述態樣中之任一者之各種實施例中，個體經鑑別為需要治療。在本文中所敍述態樣中之任一者之各種實施例中，個體患有或經鑑別為患有增加之發炎。在本文中所敍述態樣中之任一者之各種實施例中，個體具有或經鑑別為具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因(例如在TMPRSS6 核酸分子之核苷酸位置2321處具有G或C)，且相對於參照患有增加之發炎。在本文中所敍述態樣中之任一者之各種實施例中，方法包含向個體投與IL-6拮抗劑。在本文中所敍述態樣中之任一者之各種實施例中，方法包含向個體投與IL-6拮抗劑及用於貧血之療法。在本文中所敍述態樣中之任一者之各種實施例中，個體為人類。 在本文中所敍述態樣中之任一者之各種實施例中，用於貧血之療法包含投與促紅血球形成因子。在各種實施例中，促紅血球形成因子為紅血球生成素、紅血球生成刺激劑、HIF安定劑及補充鐵中之一或多者。 在各種實施例中，增加之發炎之特徵在於相對於參照組，增加之IL-6及/或CRP含量(例如如藉由習知CRP分析或高敏感性分析(hsCRP)所量測，以上兩者偵測CRP，但在分析效能方面不同)。在各種實施例中，增加之發炎表徵為IL-6大於約5 pg/ml。在各種實施例中，增加之發炎表徵為CRP大於約2 mg/L。 在本文中所敍述態樣中之任一者之各種實施例中，IL-6拮抗劑以有效地中和發炎之量投與。在各種實施例中，有效地中和發炎之量使IL-6降低至小於約15 pg/ml、小於約10 pg/ml或小於約5 pg/ml。在各種實施例中，有效地中和發炎之量使CRP降低至小於約2 mg/L或小於約0.2 mg/L。 在本文中所敍述態樣中之任一者之各種實施例中，投與IL-6拮抗劑或抗IL-6抗體減少EPO之劑量。在某些實施例中，EPO之劑量減少約40 IU/kg/週、約50 IU/kg/週、約80 IU/kg/週、約100 IU/kg/週或大於100 IU/kg/週。在各種實施例中，投與IL-6拮抗劑或抗IL-6抗體降低經增加EPO劑量之副作用。 在一個實施例中，在存在或不存在用於貧血之標準治療下治療患有慢性腎病之患者。詳言之，在存在或不存在用於貧血之治療(例如投與EPO、ESA、HIF安定劑、補充鐵或紅細胞輸注)下，向患有與慢性腎病相關之貧血之個體提供抑制IL-6生物活性或表現之藥劑。用於貧血之治療藉由刺激紅血球生成或紅血球產生起作用。因此，亦可投與增加紅血球或其祖細胞之生長或增殖及/或降低紅血球或其祖細胞之細胞死亡的藥劑。紅血球祖細胞包括例如造血幹細胞、常見骨髓祖細胞、前紅血球母細胞、紅血球母細胞、網狀紅血球或能夠分化或成熟化成紅血球之任何細胞。 藉由阻斷IL-6或其受體(gp80)彼此結合或阻斷其信號傳導或表現來抑制IL-6生物活性之藥劑可以醫藥組合物形式提供至患有與慢性腎病相關之貧血之個體，其中醫藥組合物包含有效量之藥劑、用於治療貧血之藥劑(例如EPO、ESA、HIF脯胺醯基-羥化酶抑制劑、補充鐵)及適合之賦形劑。在一個實施例中，藥劑為降低個體中之IL-6多肽或核酸分子之含量或活性、或抑制藉由IL-6受體活化觸發之胞內信號傳導的IL-6拮抗劑或抗IL-6抗體。抗IL-6抗體(例如MEDI5117)可與用於貧血之治療(例如投與EPO、ESA、HIF安定劑、補充鐵)組合而投與。用於貧血之治療之方法視患者之TMPRSS6 基因型及患者之發炎狀態而變化。在用於貧血之治療(例如投與EPO、ESA、HIF安定劑、補充鐵)之情況下，針對在核苷酸位置2321處包含G或C之TMPRSS6 之主要對偶基因(編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽)為同型接合或異型接合的且具有升高之發炎標記物(例如IL-6及/或CRP)含量之患者經投與IL-6拮抗劑或抗IL-6抗體，其降低IL-6多肽之含量或活性。針對在核苷酸位置2321處包含A或T之TMPRSS6 之次要對偶基因(編碼在胺基酸位置736處包含纈胺酸之TMPRSS6 多肽)為同型接合之患者不需要抗IL-6療法來補充用於貧血之治療。用於貧血之治療之方法可視慢性腎病之階段、患者年齡、健康狀況及物理條件而變化。 在另一態樣中，提供適用於表徵患有與慢性發炎相關之貧血(例如在慢性腎病中)之個體的分析。發炎標記物IL-6及CRP可藉由任何適合之方法偵測。本文中所描述之方法可個別地或以組合形式使用以用於偵測IL-6或CRP生物標記物及/或發炎病狀。在一個實施例中，相對於參照(例如來自健康對照個體之血清)之表現，發炎藉由偵測個體之生物樣本(例如血清)中之IL-6及/或CRP多肽之含量來表徵，其中IL-6及/或CRP表現之增加指示發炎。在另一實施例中，IL-6及/或CRP表現之增加指示患有與慢性腎病相關之貧血之個體將不對用於貧血之治療起反應，及/或當與IL-6拮抗劑(例如抗IL-6抗體)組合投與時，將對用於貧血之治療起反應。 在一個實施例中，IL-6及/或CRP多肽含量藉由免疫分析來量測。免疫分析通常使用抗體(或特異性結合標記物之其他藥劑)以偵測生物標記物在樣本中之存在或含量。抗體可藉由此項技術中熟知之方法(例如藉由使具有生物標記物或其片段之動物免疫)來製備。生物標記物可基於其結合特徵自樣本分離。或者，若多肽生物標記物之胺基酸序列為已知的，則多肽可經合成且用以藉由此項技術中熟知之方法產生抗體。 在各種實施例中，使用傳統的免疫分析，包括例如西方墨點；夾心免疫分析，包括ELISA及其他酶免疫分析；基於螢光之免疫分析及化學發光。濁度測定法為在液相中進行之分析，其中抗體在溶液中。抗原與抗體之結合導致吸光度變化，測量該吸光度。其他形式之免疫分析包括磁性免疫分析、放射免疫分析及即時免疫定量PCR (iqPCR)。其他偵測方法包括液相層析及質譜分析。 可在固體基板(例如晶片、珠粒、微流體平台、膜)上或在任何支持抗體與標記物結合及後續偵測之其他形式上進行免疫分析。可一次偵測單一標記物或可使用多重格式。多重免疫分析可能涉及平面微陣列(蛋白質晶片)及基於珠粒之微陣列(懸浮陣列)。 選擇患有鑑別為具有增加之IL-6及/或CRP多肽含量之貧血之慢性腎病患者用於使用降低IL-6表現或活性之藥劑(例如抗IL-6抗體)之治療與貧血之治療組合。用本發明方法治療之患者可藉由偵測治療後血紅素、血容比、紅血球生成素劑量、IL-6及/或CRP表現之變化來監測。顯示IL-6及/或CRP表現降低及/或發炎降低之患者經鑑別為對IL-6抑制起反應。 其他態樣及實施例提供於以下編號條項中。 1. 一種治療經選擇個體之慢性發炎之方法，該方法包含向個體投與IL-6拮抗劑，其中選擇治療之個體具有一或多個編碼包含丙胺酸在胺基酸位置736之TMPRSS6 多肽之對偶基因。 2. 一種治療患有心血管疾病、心臟衰竭及/或慢性腎病之經選擇個體之發炎的方法，該方法包含向個體投與IL-6拮抗劑，其中選擇治療之個體具有一或多個編碼包含丙胺酸在胺基酸位置736之TMP RSS6 多肽之對偶基因。 3. 一種降低患有心血管疾病、心臟衰竭及/或慢性腎病之經選擇個體之發炎及死亡風險的方法，該方法包含向個體投與IL-6拮抗劑，其中個體經選擇為具有一或多個編碼包含丙胺酸在胺基酸位置736之TMPRSS6 多肽之對偶基因，且相對於參照者患有增加之發炎。 4. 一種治療患有慢性腎病之個體之貧血的方法，該方法包含向個體投與IL-6拮抗劑，其中個體經鑑別為具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因，且相對於參照患有增加之發炎。 5. 如條項1至4中任一項之方法，其中IL-6拮抗劑以有效地中和發炎之量投與。 6. 如條項1至4中任一項之方法，其中IL-6拮抗劑為抗IL-6抗體。 7. 如條項5之方法，其中該方法進一步包含向個體投與促紅血球形成因子。 8. 如條項1至4中任一項之方法，其中該方法降低個體之死亡風險。 9. 一種降低患有慢性腎病或心臟衰竭之個體之死亡風險的方法，該方法包含向個體投與IL-6拮抗劑，其中個體經鑑別為具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因，且相對於參照患有增加之發炎。 10. 一種治療患有增加之發炎的個體之貧血之方法，該方法包含： 以有效地中和個體之發炎之量投與促紅血球形成因子及抗IL-6抗體,該個體具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因。 11. 如條項1至10中任一項之方法，其中增加之發炎之特徵在於相對於參照增加之IL-6及/或CRP含量。 12. 如條項11之方法，其中增加之發炎表徵為IL-6大於約5 pg/ml、約10 pg/ml或約15 pg/ml。13. 如條項10之方法，其中增加之發炎表徵為CRP大於約2 mg/L。 14. 如條項10之方法，其中促紅血球形成因子為紅血球生成素、紅血球生成刺激劑、HIF安定劑及補充鐵中之一或多者。15. 一種在鑑別為有需要之個體中增強對EPO之反應的方法，該方法包含以有效地中和個體之發炎之量投與IL-6拮抗劑或抗IL-6抗體，從而增強個體對EPO之反應，該個體具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因。 16. 如條項15之方法，其中有效地中和發炎之抗IL-6抗體的量使IL-6降低至小於約15 pg/ml、小於約10 pg/ml或小於約5 pg/ml。 17. 如條項16之方法，其中有效地中和發炎之IL-6拮抗劑或抗IL-6抗體的量使CRP降低至小於約2 mg/L。 18. 如條項15之方法，其中投與IL-6拮抗劑或抗IL-6抗體減少EPO之劑量。 19. 如條項17之方法，其中EPO之劑量減少約40 IU/kg/週、約50 IU/kg/週、約80 IU/kg/週、約100 IU/kg/週或大於100 IU/kg/週。 20. 如條項15之方法，其中投與IL-6拮抗劑或抗IL-6抗體降低經增加EPO之副作用。 21. 一種為鑑別為有需要之個體選擇療法之方法，該方法包含： a)將個體表徵為具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因；及 b)偵測一或多種發炎標記物IL-6及CRP之含量，其中表徵指示IL-6拮抗劑應與用於貧血之療法組合投與。 22. 如條項21之方法，其中該方法進一步包含向個體投與IL-6拮抗劑及用於貧血之療法。 23. 如條項21之方法，其中用於貧血之療法包含投與促紅血球形成因子。 24. 一種用於增加鑑別為有需要之個體中之紅血球或其祖細胞的增殖或存活之方法，該方法包含向個體投與IL-6拮抗劑及促紅血球形成因子，其中個體經鑑別為具有編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽之一或多個對偶基因，且其中個體相對於參照患有增加之發炎。 25. 如條項24之方法，其中該方法降低紅血球或其祖細胞之細胞死亡。 26. 如條項24之方法，其中祖細胞為造血幹細胞、前紅血球母細胞、紅血球母細胞或網狀紅血球。 27. 如條項15至24中任一項之方法，其中個體患有慢性腎病。 28. 如條項15至24中任一項之方法，其中個體患有貧血。 29. 如條項28之方法，其中貧血為癌症貧血、慢性自體免疫疾病中之貧血、慢性發炎疾病中之貧血或代謝症候群中之貧血。 30. 如條項15至24中任一項之方法，其中IL-6拮抗劑以有效地中和發炎之量投與。 31. 如條項15至24中任一項之方法，其中IL-6拮抗劑為抗IL-6抗體。 32. 如條項15至24中任一項之方法，其中增加之發炎之特徵在於相對於參照增加之IL-6及/或CRP含量。 33. 如條項15至24中任一項之方法，其中增加之發炎表徵為IL-6大於約5 pg/ml、約10 pg/ml或約15 pg/ml。34. 如條項15至24中任一項之方法，其中增加之發炎表徵為CRP大於約2 mg/L。 35. 如條項15至24中任一項之方法，其中有效地中和發炎之量使IL-6降低至小於約10 pg/ml或小於約5 pg/ml。 36. 如條項15至24中任一項之方法，其中有效地中和發炎之量使CRP降低至小於約2 mg/L。 37. 如條項15至24中任一項之方法，其中促紅血球形成因子為紅血球生成素、紅血球生成刺激劑、HIF安定劑及補充鐵中之一或多者。 38. 如條項24之方法，其中投與IL-6拮抗劑減少EPO之劑量。 39. 如條項38之方法，其中IL-6拮抗劑為抗IL-6抗體。 40. 如條項38之方法，其中EPO之劑量減少約40 IU/kg/週、約50 IU/kg/週、約80 IU/kg/週、約100 IU/kg/週或大於100 IU/kg/週。 41. 如條項23之方法，其中投與IL-6拮抗劑降低經增加EPO之副作用。 42. 如條項1至40中任一項之方法，其中對偶基因在TMPRSS6 聚核苷酸之2321位置處包含G。 43. 如條項1至42中任一項之方法，其中IL-6拮抗劑為具有一或多個選自以下核酸序列之CDR之抗IL-6抗體： SNYMI (SEQ ID NO: 12)； DLYYYAGDTYYADSVKG (SEQ ID NO: 13)； WADDHPPWIDL (SEQ ID NO:14)； RASQGISSWLA (SEQ ID NO: 15)； KASTLES (SEQ ID NO: 16)；及 QQSWLGGS (SEQ ID NO: 17)。 44. 如條項42之方法，其中抗IL-6抗體具有包含序列SNYMI (SEQ ID NO: 12)之重鏈CDR1；包含序列DLYYYAGDTYYADSVKG (SEQ ID NO: 13)之重鏈CDR2；包含序列WADDHPPWIDL (SEQ ID NO: 14)之重鏈CDR3；包含序列RASQGISSWLA (SEQ ID NO: 15)之輕鏈CDR1；包含序列(SEQ ID NO: 16)之輕鏈CDR2；及包含序列QQSWLGGS (SEQ ID NO 17)之輕鏈CDR3。 45. 如條項42之方法，其中抗IL-6抗體具有包含以下序列之重鏈： 。 46. 如條項42之方法，其中抗IL-6抗體具有包含以下序列之輕鏈： 。 47. 如條項42之方法，其中抗IL-6抗體為MEDI5117。 48. 如條項1至47中任一項之方法，其中個體為人類。 5.13.2 用於治療心腎症候群之方法 在其他態樣及實施例中，提供用於治療心腎症候群之組合物及方法。 此等態樣及實施例至少部分地基於以下發現：心腎症候群之嚙齒動物模型中心臟損傷之抗IL-6治療具有與標準護理治療等效之作用。如下文更詳細報導，心肌梗塞後，心腎症候群之嚙齒動物模型用抗IL-6或標準護理療法(ACE抑制劑、培哚普利)治療。治療後，量測心臟組織中之射血分數、心肌收縮力及纖維化組織之百分比。與用對照治療劑治療之個體組中之含量相比，用抗IL-6治療之個體組及用標準護理療法治療之個體組中之射血分數之程度均增加。與用對照治療劑治療之個體組中之含量相比，用抗IL-6治療之組及用標準護理療法治療之組中之心肌收縮性均增加。與用對照治療劑治療之個體組中之量相比，用抗IL-6治療之組及用標準護理療法治療之組中之纖維化組織的量均減少。此外，在用抗IL-6治療之個體組及用標準護理療法治療之個體組中，射血分數之程度及纖維化組織之量類似。結果表明在治療嚙齒動物模型中之心腎症候群中，抗IL-6療法具有與標準護理療法等效之功效。 此等態樣及實施例進一步至少部分地基於以下發現：鑑別為在心肌梗塞後患有心腎症候群且具有升高之IL-6含量的患者尤其具有增加之心血管死亡(包括心臟衰竭)風險。不受理論束縛，IL-6可在心腎症候群之發展及/或進程中起病因作用。因此心肌梗塞後具有升高之IL-6含量之患者或患有心腎症候群及升高之IL-6含量之患者將可能受益於IL-6抑制。 因此，提供用於治療患有心腎症候群之個體之心臟及/或腎損傷的治療方法，其涉及向個體投與IL-6拮抗劑。在一些實施例中，在存在或不存在用於心腎症候群之標準治療下，為患有心腎症候群之個體之心臟及/或腎損傷進行治療。亦提供用於表徵心肌梗塞後患者之心血管死亡風險之方法，該方法涉及在獲自該患者之生物樣本中偵測IL-6含量之增加。 在一個態樣中，提供治療患有心腎症候群之個體之心臟及/或腎損傷的方法，該方法涉及向個體投與IL-6拮抗劑。 在另一態樣中，提供增加患有心腎症候群之個體之心臟功能的方法，該方法涉及向個體投與IL-6拮抗劑。 在再一態樣中，提供降低患有心腎症候群之個體之纖維化的方法，該方法涉及向個體投與IL-6拮抗劑。 在本文中所敍述態樣中之任一者之各種實施例中，該方法進一步涉及向個體投與標準護理療法。在各種實施例中，標準護理療法為血管收縮素轉化酶(ACE)抑制劑。 在本文中所敍述態樣中之任一者之各種實施例中，心臟功能增加之特徵在於相對於參照組，個體之射血分數及/或心肌收縮力之增加。在本文中所敍述態樣中之任一者之各種實施例中，纖維化降低之特徵在於相對於參照組，來自個體之組織樣本中纖維化組織之百分比之降低。在各種實施例中，纖維化係在心臟組織中。 在本文中所敍述態樣中之任一者之各種實施例中，個體患有心臟及/或腎損傷。在本文中所敍述態樣中之任一者之各種實施例中，個體患有心臟損傷，隨後患有腎損傷。 在另一態樣中，本發明提供一種在個體中鑑別心肌梗塞後個體之心血管死亡(例如心臟衰竭)風險增加的方法，該方法涉及相對於參照組，量測來自個體之樣本中IL-6聚核苷酸或多肽中之一或多者之含量，其中IL-6聚核苷酸或多肽中之一或多者的含量增加時，指示心血管死亡風險增加。 在再一態樣中，本發明提供一種在個體中表徵心肌梗塞後個體之心血管死亡(例如心臟衰竭)風險的方法，該方法涉及量測相對於參照來自個體之樣本中IL-6聚核苷酸或多肽中之一或多者之含量，其中增加之IL-6聚核苷酸或多肽中之一或多者的含量指示增加之心血管死亡風險。 在本文中所敍述態樣中之任一者之各種實施例中，個體患有心腎症候群、心臟衰竭、慢性腎病或無心腎病變。在本文中所敍述態樣中之任一者之各種實施例中，個體經鑑別為在心肌梗塞後約一個月患有心腎症候群、心臟衰竭、慢性腎病或無心腎病變。 在另一態樣中，本發明提供一種治療患有心腎症候群之經選擇個體之心臟及/或腎損傷的方法，該方法涉及向個體投與IL-6拮抗劑，其中針對治療，個體藉由偵測相對於參照來自個體之生物樣本中增加之IL-6聚核苷酸或多肽中之一或多者的含量經選擇。 在再一態樣中，本發明提供一種降低患有心腎症候群之經選擇個體之心血管死亡(例如心臟衰竭)風險的方法，該方法涉及向個體投與IL-6拮抗劑，其中個體藉由偵測相對於參照來自個體之生物樣本中增加之IL-6聚核苷酸或多肽中之一或多者的含量來選擇。在本文中所敍述態樣中之任一者之各種實施例中，個體患有心肌梗塞。 在本文中所敍述態樣中之任一者之各種實施例中，IL-6拮抗劑為抗IL-6抗體。在各種實施例中，抗IL-6抗體為MEDI5117。 在本文中所敍述態樣中之任一者之各種實施例中，生物樣本為血漿樣本或血清樣本。在本文中所敍述態樣中之任一者之各種實施例中，個體為人類。 在另一態樣中，提供用於藉由投與抑制IL-6生物活性或表現之藥劑，來治療患者之心腎症候群及/或降低此類患者之死亡或心臟衰竭風險的方法。在一個實施例中，在存在或不存在用於心腎症候群之標準治療(例如血管收縮素轉化酶(ACE)抑制劑)下治療患有心腎症候群之患者。詳言之，將抑制IL-6生物活性或表現之藥劑提供至患有心腎症候群之個體(例如投與抗IL-6抗體)。 在另一態樣中，提供在患有心腎症候群之個體中增加心臟功能之方法及降低纖維化的方法。方法包含向個體投與抑制IL-6生物活性或表現之藥劑。在一些實施例中，心臟功能增加之特徵在於相對於參照(例如健康對照個體之射血分數)，個體射血分數之增加，或相對於參照(例如健康對照個體之心肌收縮性)，心肌收縮性(例如dP/dt最大 )之增加。在一些實施例中，纖維化降低之特徵在於相對於參照(例如獲自健康對照個體之組織樣本)，來自個體之組織樣本中纖維化組織之百分比的降低。在一個實施例中，纖維化係在心臟組織中。 藉由阻斷IL-6或其受體(gp80)彼此結合或阻斷其信號傳導或表現來抑制IL-6生物活性之藥劑可以醫藥組合物形式提供至患有心腎症候群之個體，其中醫藥組合物包含有效量之藥劑及適合之賦形劑。在一個實施例中，藥劑為降低個體中之IL-6多肽或聚核苷酸之含量或活性、或抑制藉由IL-6受體活化觸發之胞內信號傳導的IL-6拮抗劑或抗IL-6抗體。可投與抗IL-6抗體(例如MEDI5117)。用於心腎症候群之治療之方法可視心腎症候群之階段、患者年齡、健康狀況及物理條件而變化。 在各種實施例中，用IL-6拮抗劑治療患有心腎症候群之個體。此外，心肌梗塞後具有增加之心血管死亡及/或心臟衰竭之風險的個體可藉由表徵個體中之血漿IL-6含量來鑑別。具有升高之IL-6含量之個體具有增加之心血管死亡及/或心臟衰竭之風險。對於用IL-6拮抗劑進行之治療，可選擇此類個體。另外，可選擇患有心腎症候群且具有增加之IL-6含量之個體，包括已罹患心肌梗塞之此類個體，以用於治療。為治療選擇後，此類個體可經投與此項技術中已知之幾乎任何的IL-6拮抗劑。適合之IL-6拮抗劑包括例如IL-6拮抗劑、商業上可獲得之IL-6拮抗劑、使用此項技術中熟知之方法開發之IL-6拮抗劑，及針對與IL-6R相關之胞內信號傳導系統之拮抗劑。 在另一態樣中，提供用於表徵心肌梗塞後個體之心血管死亡、心臟衰竭及/或死亡之風險的分析。分析提供對獲自個體之生物樣本中之IL-6的偵測。IL-6可藉由任何適合之方法偵測。在一個實施例中，心血管死亡或心臟衰竭之風險藉由偵測相對於參照(例如來自健康對照個體或來自不具有心-腎病變之對照個體之血清或血漿)中之表現，個體之生物樣本(例如血清或血漿)中之IL-6多肽含量來表徵，其中IL-6之增加指示增加之心血管死亡或心臟衰竭之風險。可選擇鑑別為具有增加之心血管死亡、心臟衰竭或死亡之風險的個體以用於治療。在另一實施例中，對於用IL-6拮抗劑(例如抗IL-6抗體)進行之治療，選擇患有心腎症候群且具有增加之IL-6含量之個體。 在一個實施例中，量測IL-6聚核苷酸含量。IL-6聚核苷酸之含量可藉由標準方法量測，該等標準方法諸如定量PCR、北方墨點、微陣列、質譜分析及原位雜交。 在一個實施例中，量測IL-6多肽含量。IL-6多肽之含量可藉由標準方法(諸如藉由免疫分析)量測。免疫分析通常使用抗體(或特異性結合標記物之其他藥劑)以偵測生物標記物在樣本中之存在或含量。抗體可藉由此項技術中熟知之方法(例如藉由使具有生物標記物或其片段之動物免疫)來製備。生物標記物可基於其結合特徵自樣本分離。或者，若多肽生物標記物之胺基酸序列為已知的，則多肽可經合成且用以藉由此項技術中熟知之方法產生抗體。 在各種實施例中，分析採用傳統的免疫分析，包括(例如)西方墨點；夾心免疫分析，包括ELISA及其他酶免疫分析；基於螢光之免疫分析及化學發光。濁度測定法為在液相中完成之分析，其中抗體在溶液中。抗原與抗體之結合導致吸光度之變化，該吸光度經量測。其他形式之免疫分析包括磁性免疫分析、放射免疫分析及即時免疫定量PCR (iqPCR)。其他偵測方法包括液相層析及質譜分析。 可在固體基板(例如晶片、珠粒、微流體平台、膜)上或在支持抗體與標記物之結合及後續偵測之任何其他形式上進行免疫分析。可一次偵測單標記物或可使用多重格式。多重免疫分析可涉及平面微陣列(蛋白質晶片)及基於珠粒之微陣列(懸浮陣列)。 對於用降低IL-6表現或活性之藥劑(例如抗IL-6抗體)進行之治療，選擇經鑑別為具有增加之IL-6多肽含量之心腎症候群患者。治療劑可與用於心腎症候群之標準治療(例如ACE抑制劑)組合投與。用本發明方法治療之患者可藉由偵測治療後IL-6之變化來監測。 其他態樣及實施例提供於以下經編號條項中。 1.一種治療患有心腎症候群之個體之心臟及/或腎損傷的方法，該方法包含向個體投與IL-6拮抗劑。 2. 一種增加患有心腎症候群之個體之心臟功能的方法，該方法包含向個體投與IL-6拮抗劑。 3. 一種降低患有心腎症候群之個體之纖維化的方法，該方法包含向個體投與IL-6拮抗劑。 4. 如條項2之方法，其中心臟功能增加之特徵在於相對於參照組，個體射血分數之增加。 5. 如條項3之方法，其中纖維化係在心臟組織中。 6. 如條項3或5之方法，其中纖維化降低之特徵在於相對於參照組，來自個體之組織樣本中纖維化組織之百分比之降低。 7. 如條項1至6中任一項之方法，其中個體患有心臟及/或腎損傷。 8. 如條項1至7中任一項之方法，其中個體患有心臟損傷，隨後患有腎損傷。 9. 如條項1至8中任一項之方法，其進一步包含向個體投與標準護理療法。 10. 如條項1至9中任一項之方法，其中標準護理療法為血管收縮素轉化酶(ACE)抑制劑。 11. 一種在個體中鑑別心肌梗塞後個體之增加之心血管死亡風險的方法，該方法包含量測相對於參照來自個體之樣本中IL-6聚核苷酸或多肽中之一或多者之含量，其中增加之IL-6聚核苷酸或多肽中之一或多者的含量指示增加之心血管死亡風險。 12. 一種在個體中表徵心肌梗塞後個體之心血管死亡風險之方法，該方法包含量測相對於參照來自個體之樣本中IL-6聚核苷酸或多肽中之一或多者之含量，其中增加之IL-6聚核苷酸或多肽中之一或多者的含量指示增加之心血管死亡風險。 13. 如條項11或12之方法，其中個體患有心腎症候群、心臟衰竭、慢性腎病或無心腎病變。 14. 如條項11至13中任一項之方法，其中個體經鑑別為在心肌梗塞後約一個月患有心腎症候群、心臟衰竭、慢性腎病或無心腎病變。 15. 一種治療患有心腎症候群之經選擇個體之心臟及/或腎損傷的方法，該方法包含向個體投與IL-6拮抗劑，其中針對治療，個體藉由偵測相對於參照來自個體之生物樣本中增加之IL-6聚核苷酸或多肽中之一或多者的含量經選擇。 16. 一種降低患有心腎症候群之經選擇個體之心血管死亡風險的方法，該方法包含向個體投與IL-6拮抗劑，其中個體藉由偵測相對於參照來自個體之生物樣本中增加之IL-6聚核苷酸或多肽中之一或多者的含量經選擇。 17. 如條項15或16之方法，其中個體已患有心肌梗塞。 18. 如條項1至10或15至17中任一項之方法，其中IL-6拮抗劑為抗IL-6抗體。 19. 如條項18之方法，其中抗IL-6抗體為MEDI5117。 20. 如條項11至19中任一項之方法，其中生物樣本為血漿樣本。 21. 如條項1至20中任一項之方法，其中個體為人類。 5.14 實例 以下實例以說明而非限制方式提供。 5.14.1 實例1： 慢性腎病患者中之EPO劑量及總存活率僅與具有TMPRSS6 SNP rs855791主要對偶基因之至少一個複本之患者中的血清IL-6及CRP含量相關 肽激素海帕西啶在全身鐵恆定中起主要作用。Hentze等人,Cell 142:24-38 (2010)。已知海帕西啶表現受TMPRSS6 基因之產物間質蛋白酶-2影響，該間質蛋白酶-2為II型跨膜絲胺酸蛋白酶。已顯示TMPRSS6 基因之常見變異體與鐵狀態相關，Benyamin等人,Nature Genetics 41(11):1173-1175 (2009)，且已顯示TMPRSS6 基因之某些突變引起鐵難治性缺鐵性貧血IRIDA)，Finberg等人,Nature Genetics 40(5):569-571 (2008)。SNP rs855791 (2321G→A；A736V)為TMPRSS6 基因之天然存在之變型，其在海帕西啶表現及血液血紅素含量方面與天然存在之變型相關。 為判定TMPRSS6 rs855791 SNP處之基因型是否預測末期腎病中之貧血程度，結合新確定之SNP基因分型來分析先前在患有慢性腎病之患者之臨床研究中收集的資料。由於海帕西啶表現亦由IL-6調節，Casanovas等人,PLOS Computational Biol. 10(1):e1003421 (2014)，亦分析資料以判定血清IL-6含量是否可預測末期腎病中之貧血程度。方法 基於普遍之透析準則、鐵蛋白＞100 ng/mL及Hb ＞10 mg/dL，將來自入選於MIMICK1、MIMICK2 (發炎標記物在慢性腎病中之定位)及MIA (營養不良、發炎及動脈粥樣硬化)群組中之N=257患者之資料管理至N=208，以選擇在無缺鐵性貧血之情況下且在無經標記貧血之情況下血液透析穩定的患者，從而不包含具有可自血紅素含量分離鐵輸送之因子之患者，該等群組在2003年10月-2004年9月之時間期期間在Stockholm-Uppsala (Sweden)區在六個透析單元中招募。 將所有患者臨床資料，包括以IU/kg/週為單位之紅血球生成素(EPO)劑量、以pg/ml為單位之IL-6血清含量、以mg/L為單位之CRP血清含量、以月為單位之存活及SNP rs855791處之TMPRSS6 基因型校對且使用統計分析軟體(SPSS統計桌上型；IBM)分析。所研究之TMPRSS6 對偶基因及其核苷酸及胺基酸指示在表1下。 將群組分成rs855791子組(同型接合AA、異型接合AG及同型接合GG)，且將各基因型組分成血清IL-6含量(例如相較於＞ 10 pg/ml，IL-6 ＜ 5pg/ml，且相較於＞ 15pg/ml，IL-6 ＜ 5pg/ml)或血清CRP含量(相較於＞ 2 mg/L，CRP ＜ 2 mg/L)之三分位或四分位。比較在頂部及底部三分位及四分位中之EPO劑量。進行在藉由斯氏T測試(Students T-Test)之基因型組內及在藉由ANOVA之組之間的統計學家分析。結果 由於各患者之EPO劑量已由治療醫師滴定以獲得正常血紅素含量，因此EPO劑量可用作基礎貧血程度之代理。發現針對次要對偶基因為同型接合(A/A)之個體中之EPO劑量對IL-6之變型相對不敏感(圖1A；左圖)。然而，具有主要對偶基因之至少一個複本之個體-針對主要對偶基因(G)為異型接合(A/G)或同型接合(G/G)之患者-中之EPO劑量對個體IL-6含量敏感(圖1B；右圖)。在此等後面個體中，增加之血清IL-6含量(例如＞ 5 pg/ml)與增加之EPO劑量相關。 不受特定理論束縛，次要對偶基因下之純合性移除IL-6對鐵輸送之影響。因此，與IL-6含量無關，此等患者(A/A)中之EPO劑量大致相同。 與IL-6含量無關，針對TMPRSS6 rs855791次要對偶基因(A)為同型接合之個體展示類似之死亡(圖2A)。然而，具有主要對偶基因之至少一個複本之個體-針對主要對偶基因(G)為異型接合或同型接合之患者-之存活率根據IL-6含量變化(圖2B)。實際上，回應於慢性腎病5期透析個體中之升高的IL-6含量，TMPRSS6 之G對偶基因賦予更高之各種原因之死亡。在具有主要對偶基因(G)之至少一個複本之個體中，與＜ 5pg/ml之IL-6含量(亦即低位IL-6)相比，≥ 5pg/ml之IL-6含量 (亦即中位及最高位IL-6)與增加之死亡率相關(圖2B)。 在針對主要對偶基因(G)為異型接合或同型接合之個體中，急性期反應物CRP-發炎標記物-之含量亦與增加之EPO劑量相關，但在針對次要對偶基因為同型接合之患者中不如此(圖3)。論述 如圖1中所展示，在具有TMPRSS6 rs855791 SNP處之主要對偶基因之至少一個複本之患者中，基礎貧血程度-量測為臨床上滴定之EPO劑量-僅與IL-6含量相關。在此等患者中，血清IL-6含量愈高，所需EPO劑量愈高(圖1B)。相反，具有次要對偶基因之兩個複本之患者的貧血程度不與血清IL-6含量相關(圖1A)。 類似地，在具有TMPRSS6 SNP rs855791處之主要對偶基因之至少一個複本的患者中，總存活率僅與IL-6含量相關。在具有TMPRSS6 rs855791主要對偶基因之至少一個複本之個體中，存活率成反比地與血清IL-6含量相關，其中血清IL-6含量之最高位中之患者比IL-6含量之最低位中之彼等患者具有統計學上顯著更壞的存活率(圖2B)。相反，針對rs855791處之次要對偶基因為同型接合之患者之總存活率不受IL-6含量影響(圖2A)。 不意欲受理論束縛，在具有TMPRSS6 主要對偶基因之至少一個複本之患者中，血清IL-6之增加可促進海帕西啶表現增加，從而增加貧血。增加之死亡風險為失調之鐵代謝、所得貧血及/或增加之紅血球生成刺激劑(諸如EPO)劑量之結果。若此等相關性反映因果關係，則其提昇了以下可能性：在患有慢性腎病之患者中，降低之IL-6含量或IL-6信號傳導可降低貧血，減少所需EPO劑量，且增加存活率，但僅在具有TMPRSS6 rs855791主要對偶基因之至少一個複本之彼等患者中，且在具有升高之血清IL-6含量之彼等患者中具有最大作用。 5.14.2 實例2： 急性心肌梗塞後之死亡風險及心臟衰竭風險僅與具有TMPRSS6 SNP rs855791主要對偶基因之至少一個複本之患者中的IL-6血清含量相關 為判定在患有急性疾病而非慢性疾病之患者中TMPRSS6 rs855791基因型是否影響IL-6敏感性，結合新確定之SNP基因分型來分析先前在因急性冠狀動脈症候群住院之患者之臨床研究中收集的資料。方法 自先前入選於血小板抑制及患者結果(PLATO)之多中心研究中之個體分析資料。若患者因急性冠狀動脈症候群(在先前24小時期間具有症狀發作)住院，則其有資格入選於PLATO中。在心肌梗塞後30天開始之此等個體中量測死亡率及心臟衰竭之存在。結果 針對TMPRSS6 rs855791 SNP次要對偶基因(A)為同型接合之個體之死亡不與IL-6之變型相關(圖4A)。然而，回應於心肌梗塞後個體中之升高之IL-6含量，主要對偶基因(G)之一或兩個複本賦予更高之各種原因之死亡(圖4B)。因此，TMPRSS6 調節心肌梗塞後之IL-6介導之死亡風險。 亦在心肌梗塞後30天開始之入選於PLATO中之個體中量測TMPRSS6 基因型對IL-6介導之心臟衰竭風險的影響。在針對次要對偶基因(A)為同型接合之個體之心臟衰竭不與IL-6之變型相關(圖5A)。然而，回應於心肌梗塞後個體中之升高之IL-6含量，TMPRSS6 之G對偶基因賦予更高之心臟衰竭速率(圖5B)。因此，TMPRSS6 調節心肌梗塞後之IL-6介導之心臟衰竭風險。論述 此等資料表明TMPRSS6 基因型、IL-6含量及不利臨床結果之間的相關性不限於患有慢性腎病之患者。不意欲受理論束縛，在具有TMPRSS6 主要對偶基因之至少一個複本之患者中，血清IL-6增加可驅使海帕西啶表現增加，隨後心肌細胞中鐵之螯合作用增加，繼之以鐵介導之細胞毒性。若此等相關性反映因果關係，則其提昇了以下可能性：降低之IL-6含量或IL-6信號傳導可降低患有急性冠狀動脈症候群之患者之心臟衰竭及死亡，但僅在具有TMPRSS6 rs855791主要對偶基因之至少一個複本之彼等患者中，且在具有升高之血清IL-6含量之彼等患者中具有最大作用。 5.14.3 實例3： 關於源於iPS之人類心肌細胞之活體外研究確認TMPRSS6 基因型與IL-6介導之細胞毒性之間的因果關係 雖然實例1及2中所觀測之相關性暗示在具有TMPRSS6 rs855791主要對偶基因之至少一個複本、升高之IL-6含量及貧血或海帕西啶介導之細胞毒性之患者中，降低之IL-6介導之信號傳導應提供臨床效益，但所觀測相關性不能證明因果關係。因此，在源於人類誘導之多能性細胞之心肌細胞(iPS-CMs)中進行實驗以查詢BMP及BMP加IL-6對海帕西啶表現及細胞針對局部缺血損傷之易感性的作用，該等心肌細胞用TMPRSS6 之變異體轉染。 5.14.3.1 方法源於人類 iPS 之 心肌細胞之培養 - 將iCell心肌細胞(Cellular Dynamics International，CDI Inc.)塗於具有iCell心肌細胞接種培養基(CDI Inc.)之0.1%明膠塗佈之6孔或96孔細胞培養盤上。接種後四十八小時，用維持培養基(CDI Inc.)替代接種培養基。每隔一天至進行實驗之天數更換維持培養基。經模擬之局部缺血 / 再充氧方案 - 如先前所報導，藉由用「局部缺血緩衝液」替代細胞培養基，使iPS心肌細胞經歷經模擬之局部缺血(SI)90分鐘，該局部缺血緩衝液含有118 mm NaCl、24 mm NaHCO3 、1.0 mm NaH2 PO4 、2.5 mm CaCl2 -2H2 O、1.2 mm MgCl2 、20 mm乳酸鈉、16 mm KCl、10 mm 2-去氧葡萄糖(pH調節至6.2)(Das, A., Xi, L., 及Kukreja, K. C. (2005)J. Biol. Chem . 280: 12944-12955；Das A, Smolenski A, Lohmann SM, Kukreja RC. (2006)J. Biol Chem. 281(50):38644-52)。在整個SI時間期期間調節1-2% O2 及5% CO2 之三氣培育箱中在37℃下培育細胞。藉由在常氧條件下用正常細胞培養基替代局部缺血緩衝液來實現再充氧(RO)。細胞分別在再充氧2或18小時後壞死。如上，iCells經歷4小時SI及24小時RO。細胞活力及細胞凋亡之評估 -進行錐蟲藍排除分析以分析如先前所報導之細胞壞死(Das, A., Xi, L., 及Kukreja, K. C. (2005)J. Biol. Chem . 280, 12944-12955；Das A, Smolenski A, Lohmann SM, Kukreja RC. (2006)J. Biol. Chem . 281(50):38644-52)。iCell 心肌細胞之轉染 -在接種後第8天，用新鮮之維持培養基替代培養基且將細胞培育4小時。根據製造商說明書(Promega Corp., Madison, WI)使用ViaFectTM 轉染試劑，用pCMV6-XL5 TMPRSS6 (K523)或pCMV6-XL5 TMPRSS6 (K523)V763A轉染細胞。轉染48小時後，使細胞經歷其他實驗。西方墨點分析 -如先前所描述進行西方墨點(Das, A., Xi, L., 及Kukreja, K. C. (2005)J. Biol. Chem . 280, 12944-12955；Das A, Smolenski A, Lohmann SM, Kukreja RC. (2006)J. Biol. Chem . 281(50):38644-52)。用裂解緩衝液(Cell Signaling, MA)自細胞提取總可溶性蛋白。在4℃下以10,000 × g離心勻漿5分鐘，且回收清液層。由12%丙烯醯胺凝膠分離蛋白質(來自各樣本之50 μg)且將其轉移至硝基纖維素膜，且接著在TBST (10 mm Tris-HCl、pH 7.4，100 mm NaCl及0.1% Tween 20)中用5%脫脂乳粉阻斷1小時。隨後對於各別蛋白質中之每一者，將家兔單株/多株或山羊多株初級抗體以1:1000之稀釋與膜一起培育過夜，該等各別蛋白質亦即磷酸-苄氯素(Beclin)-1 (Ser93) (D9A5G)家兔單抗、苄氯素-1、SQSTM1/p62、LC3A/B (D3U4C) XP®家兔單抗、磷酸-Akt (Ser473) (D9E) XP®家兔單抗、Akt (pan) (C67E7)家兔單抗、磷酸-S6核糖體蛋白(Ser240/244) (D68F8) XP®家兔單抗、S6核糖體蛋白(5G10)家兔單抗(來自Cell Signaling, MA)、抗間質蛋白酶2 (TMPRSS6)及抗SLC40A1 (運鐵素) (來自Abcam Company, MA)，及山羊多株肌動蛋白-HRP (Santa Cruz Biotechnology, TX)。隨後將膜與抗家兔辣根過氧化酶結合之二級抗體(1:2000稀釋；Amersham Biosciences)一起培育2小時。使用化學發光系統開發墨點，且掃描條帶且藉由密度測定分析來定量。即時 PCR- 塔克曼分析 (Taqman assay) -根據製造商之方案(QIAGEN Sciences, MD, USA)使用miRNeasy微套組來分離包括小RNA之總RNA。使用Nanodrop ND-1000分光光度計(Agilent technologies, CA, USA)量測經分離RNA之濃度及純度。簡言之，使用高容量cDNA合成套組(Applied生物系統, CA, USA)用隨機六聚體將1 μg總RNA轉化成cDNA。使用以下PCR條件進行反轉錄反應：25℃持續10分鐘；37℃持續120分鐘且85℃持續5分鐘。使用塔克曼擴增子特異性探針(Applied Biosystems, CA, USA) Hamp (CGGCTCTGCAGCCTTG) (SEQ ID NO:20)在以下PCR循環條件下進行即時PCR：95℃持續10分鐘；95℃持續15秒且60℃持續60秒。將Hamp之表現標準化成GAPDH (CTTCCAGGAGCGAGATCCCGCTAA) (SEQ ID NO:21)管家基因。使用2-ΔΔCt方法分析相對基因表現。iPS 細胞之 TMPRSS6 突變誘發及轉染 -pCMV6-XL5 TMPRSS6購自Origene Technologies (Rockville, MD)，目錄號SC306623，對應於基因銀行(GenBank)寄存編號NM_153609。此純系含有引起胺基酸改變之突變，K253A。進行定點突變誘發以將位置253處之胺基酸回復成典型離胺酸(K)。確認回復後，進行定點突變誘發以引入V736A突變。使用Agilent Technologies QuikChange II XL定點突變誘發套組(Santa Clara, CA；目錄號200521)進行所有突變誘發反應。對所有載體定序以確認。所使用之引子序列為：反義(as)TMPRSS6 E253K GCATGAGGTCCTTGGGGCCCTGCAG (SEQ ID NO:22)；正義(s) TMPRSS6 E253K CTGCAGGGCCCCAAGGACCTCATGC (SEQ ID NO:23)；反義(as) TMPRSS6 V736A CCTGGTAGCGATAGGCCTCGCTGCACAGG (SEQ ID NO:24)；正義(s) TMPRSS6 V736A CCTGTGCAGCGAGGCCTATCGCTACCAGG (SEQ ID NO:25)。 5.14.3.2 結果 在基線下人類iPS-CMs僅最低限度地表現間質蛋白酶-2。分別仿效同型接合主要對偶基因及同型接合次要對偶基因心肌細胞，將細胞用促進以下之組成性表現的構築體轉染：由TMPRSS6 rs855791SNP主要對偶基因編碼之間質蛋白酶-2 736A或由次要對偶基因編碼之間質蛋白酶-2 736V。 海帕西啶表現藉由BMP6/SMAD及IL-6/STAT信號傳導路徑調節，其中BMP及IL-6兩者經由其各別受體起作用以促進海帕西啶表現增加。Casanovas等人,PLOS Comp. Biol . 10(1):e1003421 (2014)。活體外用信號傳導路徑-重組BMP2及IL-6-之促效劑或單獨用BMP2之促效劑處理主要對偶基因及次要對偶基因iPS心肌細胞，以模型化IL-6含量(或信號傳導)降低之臨床干預。不用促效劑處理對照iPS細胞。在正常氧張力(常氧)下且亦在模擬低氧隨後模擬再充氧(再灌注)之條件下量測細胞死亡率。 圖6A展示當細胞在正常氧含量下處理時之結果。僅表現TMPRSS6 rs855791次要對偶基因(「736V次要對偶基因」)之iPS心肌細胞不顯著受IL-6信號傳導之消除影響(「n.s.」)：相較於用BMP2+IL-6進行之處理，當用BMP2處理細胞時，量測為錐蟲藍陽性細胞之百分比之細胞死亡率不顯著降低。相反，當消除IL-6信號傳導時，表現TMPRSS6 rs855791主要對偶基因之iPS心肌細胞展示統計學上顯著更低之細胞死亡。 圖6B展示當細胞經歷低氧隨後經歷再充氧時之結果。相較於常氧條件，低氧/再充氧對iPS心肌細胞顯著有毒性，其中相較於在常氧條件下之約20%對照細胞，約40百分比之主要及次要對偶基因對照細胞經殺死(將圖6B與圖6A相比較)。相對於此增加之背景毒性，次要對偶基因iPS心肌細胞不顯著受IL-6信號傳導之消除影響：相較於用BMP2+IL-6進行之處理，當單獨用BMP2處理細胞時，細胞死亡率不顯著降低。相反，當消除IL-6信號傳導時，表現TMPRSS6 rs855791主要對偶基因之iPS心肌細胞展示統計學上顯著更低之細胞死亡。 5.14.3.3 論述 此等資料增強了自實例1及實例2中之臨床試驗資料之後hoc分析所得出之推斷：IL-6信號傳導之降低可有效地降低表現TMPRSS6 rs855791主要對偶基因之心肌細胞中之IL-6介導之毒性，但在僅表現次要對偶基因之心肌細胞中不如此。不意欲受理論束縛，促進主要對偶基因iPS心肌細胞中之毒性增加之IL-6可起因於海帕西啶表現之IL-6介導之增加，隨後細胞中增加之鐵螯合作用，繼之以鐵介導之細胞毒性。 5.14.4 實例4： 在基因型地類似於人類TMPRSS6 rs855791主要對偶基因同型接合子之大鼠之心腎症候群模型中，抗IL-6療法作為當前標準護理而有效 患有慢性腎病之患者，諸如入選於在實例1中分析之MIMICK研究中之彼等患者，常常罹患減弱之心臟功能，其為死亡率之主要促成者。初次慢性腎病後之此二次心臟損傷稱為4型心腎症候群(4型CRS)。 為測試抗IL-6療法是否作為治療在具有TMPRSS6 rs855791主要對偶基因之至少一個複本之CRS4患者中有效，如藉由實例1及3中之資料所表明，吾人使用基因型地類似於針對TMPRSS6 rs855791主要對偶基因為同型接合之人類之大鼠的CRS4模型。 圖7概述了研究設計。 第0週，在CRS動物中誘導心肌梗塞。在第2週進行腎切除。取而代之使對照組經歷假手術。腎切除之前，對個體進行各種評估。評估包括量測血清肌酐、腎小球濾過率、尿液中之24小時蛋白質含量、心臟超音波圖、尾套血壓，及血漿及尿液中之生物標記物。 腎切除後第1天開始治療。將動物分成三組：(i)對照治療劑，(ii)抗IL-6療法及且(iii)標準護理療法。抗IL-6療法為適用於嚙齒動物之抗IL-6抗體。標準護理療法為投與培哚普利、ACE (血管收縮素轉化酶)抑制劑。治療開始時，對所有組中之個體進行評估。評估包括量測血清肌酐、腎小球濾過率、24小時蛋白質含量及血漿中之生物標記物。 在腎切除後第3天及第7天對所有組中之個體進行評估。評估包括在第3天量測血清肌酐及血漿中之生物標記物，及在第7天量測血清肌酐、腎小球濾過率、24小時蛋白質含量、心臟超音波圖、血壓及血漿中之生物標記物。 在第6週處死個體。處死之前，對所有組中之個體進行各種評估。評估包括量測血清肌酐、腎小球濾過率、24小時蛋白質含量、血壓、血漿中之生物標記物、心臟超音波圖及壓力-容積迴路分析。處死後，亦自所有組中之個體收集組織以用於組織學評估(亦即，心臟組織之天狼星紅染色)。 圖8A-8D展示在概述於圖7中之心腎症候群模型中，以下各者之心臟射血分數：無CRS (「假」)之大鼠、用藥理學上不相關之同型對照抗體(「同型」)治療之CRS動物、用抗IL-6抗體(「IL-6 ab」)治療之CRS動物及用標準護理ACE抑制劑(「Peri」)治療之CRS動物。 圖8A展示心肌梗塞後兩週但腎切除之前且治療之前，所有組之基線射血分數程度，表明以實驗方式誘導之心肌梗塞使得心臟射血分數顯著降低。圖8B為展示腎切除後一週、治療1週後，所有組之射血分數程度的繪圖。圖8C為展示腎切除後兩週、治療2週後，所有組之射血分數程度的繪圖。圖8D為展示腎切除後四週、治療4週後，所有組之射血分數程度的繪圖。結果表述為平均+/-SEM。 治療4週後，與同型對照組相比，處理組-用抗IL-6治療之組及用標準護理ACE抑制劑療法治療之組-均展示統計學上顯著增加之射血分數程度(圖8D) (p＜0.001)。治療4週後量測之抗IL-6及標準護理組中之類似射血分數程度展示抗IL-6療法具有與ACE抑制劑培哚普利(標準護理療法)等效之功效，表明如藉由心臟射血分數之變化所量測，在保持心腎症候群模型之心臟功能方面，抗IL-6療法具有等效於標準護理療法之治療功效。 心肌收縮性之量測結果(圖9)展示抗IL-6療法亦具有等效於使用ACE抑制劑之標準護理療法之作用。治療4週後，用抗IL-6及標準護理療法治療之組之心肌收縮性顯著增加，高於對照、同型組之心肌收縮性。抗IL-6及標準護理組中之類似心肌收縮性表明如藉由收縮性所量測，在保持心腎症候群模型之心臟功能方面，抗IL-6療法具有等效於ACE抑制劑培哚普利(標準護理療法)的功效。 自所有組中之動物收集之心臟組織的纖維化量測結果亦證實抗IL-6療法具有與標準護理療法等效之作用(圖10A-10C)。心臟組織中之纖維化藉由量測以下兩個區域中之纖維化組織面積百分比來定量：「正常」區及「纖維化界限」區。實例「正常」區藉由展示於圖10A中之顯微圖中之組織切片的劃定部分所指示。顯微圖中之插圖展示「正常」區之放大視圖，展示「正常」區之小部分具有纖維化組織。「纖維化界限」區為在纖維化組織周圍之「正常」區中之組織區。 圖10B及10C中之繪圖展示當在「正常」區(圖10B)或在「纖維化界限」區(圖10C)中量測時，與同型對照組相比，來自用抗IL-6或標準護理療法治療之組中之個體的心臟組織具有顯著減少之纖維化組織面積百分比。另外，在抗IL-6及標準護理療法組中量測之纖維化組織面積百分比為類似的(均在「正常」區及「纖維化界限」區中)，指示抗IL-6具有與ACE抑制劑培哚普利(標準護理療法)等效之抗纖維化作用。 此等資料表明在基因型地類似於針對TMPRSS6 rs855791主要對偶基因為同型接合之人類之動物的心腎症候群活體內模型中，用抗IL-6劑進行之治療有效地降低心臟損傷且恢復功能。 5.14.5實例5： 在基因型地類似於人類TMPRSS6 rs855791主要對偶基因同型接合子之小鼠之急性心肌梗塞模型中，抗IL-6療法在保持心臟功能方面有效 實例2及3中之資料表明降低之IL-6含量或IL-6信號傳導可降低患有急性冠狀動脈症候群之患者之心臟衰竭及死亡，但僅在具有TMPRSS6 rs855791主要對偶基因之至少一個複本之彼等患者中，且在具有升高之血清IL-6含量之彼等患者中具有最大作用。 進行嚙齒動物研究以確定在基因型地類似於針對TMPRSS6 rs855791主要對偶基因為同型接合之人類之小鼠中，急性心肌梗塞後抗IL-6療法之作用。 圖11A及11B展示來自活體內模型之資料，在該模型中，在基因型地類似於針對TMPRSS6 rs855791主要對偶基因為同型接合之人類之小鼠中誘導心肌梗塞。對照組不接受療法。實驗組用抗鼠類IL-6抗體治療。圖11A展示用抗IL-6進行之治療在射血分數方面提供統計學上顯著之提高。圖11B展示用抗IL-6進行之治療在量測為心臟縮短分數之收縮性方面提供統計學上顯著之提高。資料資料表明在心肌梗塞後立即給出之抗IL-6療法提高了基因型地類似於具有TMPRSS6 rs855791主要對偶基因之人類患者之嚙齒動物中左心室的功能恢復。6. 以引用之方式併入 本申請案中所引用之所有公開案、專利、專利申請案及其他文獻均出於所有目的特此以全文引用之方式併入，引用的程度就如同個別地指示將各個別公開案、專利、專利申請案及其他文獻以引用之方式併入以用於所有目的一樣。7. 等效物 雖然已說明且描述各種具體實施例，但上文說明書不為限制性的。應瞭解，各種變化可在不偏離本發明之精神及範疇之情況下進行。在審閱本說明書時許多變型將對熟習此項技術者而言變得顯而易見。 Cross-reference to related applications This application claims the priority of US Provisional Application No. 62 / 199,434 filed on July 31, 2015 and US Provisional Application No. 62 / 268,788 filed on December 17, 2015, each of which is in full text Incorporated by reference. 5.1 Summary of experimental results The peptide hormone hypaxidine plays a major role in systemic iron homeostasis. Hentze et al.,Cell 142: 24-38 (2010). Hypaxidine is known to be affected byTMPRSS6 The gene product is affected by interstitial protease-2, which is a type II transmembrane serine protease. DisplayedTMPRSS6 Common variants of genes are associated with iron status, Benyamin et al.,Nature Genetics 41 (11): 1173-1175 (2009), which has shown that rs855791 SNP (2321G → A; A736V) is associated with naturally occurring variants in terms of hypaxidine performance and blood hemoglobin content. Hypaxidine performance is also involved in human iron disorders (Pietrangelo,J. Hepatology 54: 173-181 (2011)) and chronic disease anemia (ACD) (also known as inflammatory anemia (AI)). ACD is prevalent in patients with chronic infections, autoimmune diseases, cancer, and chronic kidney disease (CKD). Sun et al.,Am. J. Hematol 87 (4): 392-400 (2012). For judgmentTMPRSS6 Whether the genotype at rs855791 SNP predicts the degree of anemia in end-stage renal disease, combined with the newly determined SNP genotyping, analyze data collected in clinical studies of patients with chronic kidney disease previously. Since the performance of Hypaxidine is also regulated by IL-6, Casanovas et al.,PLOS Computational Biol. 10 (1): e1003421 (2014), to further analyze the data to determine whether serum IL-6 content can predict the degree of anemia in end stage renal disease. As described in Example 1 and as shown in FIG.TMPRSS6 In patients with at least one replica of the primary dual gene at rs855791 SNP, the degree of basal anemia-measured as a clinically titrated dose of EPO-correlates only with IL-6 content. In these patients, higher serum IL-6 levels were associated with higher required EPO doses (Figure 1B). In contrast, the degree of anemia in patients with two copies of the secondary dual gene was not related to serum IL-6 content (Figure 1A). Similarly, in havingTMPRSS6 In patients with at least one replica of the major dual gene at SNP rs855791, overall survival was only related to IL-6 content. In havingTMPRSS6 In individuals with at least one copy of the rs855791 primary dual gene, survival rates are inversely related to serum IL-6 levels, with patients at the highest levels of serum IL-6 levels compared to patients at the lowest levels of IL-6 levels With statistically significantly worse survival rates (Figure 2B). In contrast, the overall survival rate of patients with homozygous secondary genes at rs855791 was not affected by IL-6 content (Figure 2A). Without intending to be bound by theory, in havingTMPRSS6 In patients with at least one replica of the primary dual gene, an increase in serum IL-6 can promote an increase in hypaxidine performance, thereby increasing anemia. The increased risk of death is the result of dysregulated iron metabolism, the resulting anemia, and / or increased red blood cell production stimulants, such as EPO, administered for treatment. These correlations raise the possibility that reduced IL-6 content or IL-6 signaling may reduce anemia, reduce the required EPO dose, and increase the survival rate of patients with chronic kidney disease, but onlyTMPRSS6 rs855791 has the largest effect in their patients with at least one replica of the dual gene, and in their patients with elevated serum IL-6 content. To determine in patients with acute rather than chronic diseasesTMPRSS6 Whether the rs855791 genotype affects IL-6 sensitivity, in Example 2 we combined the newly determined SNP genotype to analyze the data collected in clinical studies of patients previously hospitalized for acute coronary syndromes. AgainstTMPRSS6 The death of rs855791 SNP minor dual gene (A) in individuals who are homozygous was not associated with variants of IL-6 (Figure 4A). However, in response to elevated IL-6 content in individuals after myocardial infarction, one or two copies of the primary dual gene (G) confer higher deaths of various causes (Figure 4B). therefore,TMPRSS6 Regulates IL-6-mediated death risk after myocardial infarction. Also evaluateTMPRSS6 Effects of genotypes on the risk of IL-6-mediated heart failure. Heart failure in individuals who are homozygous for the secondary dual gene (A) is not associated with a variant of IL-6 (Figure 5A). However, in response to elevated IL-6 levels in individuals after myocardial infarction,TMPRSS6 The G-dual gene confers a higher rate of heart failure (Figure 5B). therefore,TMPRSS6 Regulates the risk of IL-6-mediated heart failure after myocardial infarction. Data from Example 2 indicateTMPRSS6 The correlation between genotype, IL-6 content, and adverse clinical outcomes is not limited to patients with chronic kidney disease. Without intending to be bound by theory, in havingTMPRSS6 In patients with at least one replica of the primary dual gene, an increase in serum IL-6 can promote an increase in hypaxadine performance, followed by an increase in iron chelation in cardiac muscle cells, followed by iron-mediated cytotoxicity. These correlations raise the possibility that reduced levels of IL-6 or IL-6 signaling may reduce heart failure and death in patients with acute coronary syndromes, but onlyTMPRSS6 rs855791 has the largest effect in their patients with at least one replica of the dual gene, and in their patients with elevated serum IL-6 content. Although the correlations observed in Examples 1 and 2 strongly suggest thatTMPRSS6 rs855791 In patients with at least one replica of a major dual gene, elevated IL-6 levels, and anemia or hepasidine-mediated cytotoxicity, reduced IL-6-mediated signaling should provide clinical benefit, but the observed Relevance does not prove causality. Therefore, in Example 3, human induced pluripotent stem (iPS) cells, cardiomyocytes, were engineered to express onlyTMPRSS6 rs855791 is a major or minor dual gene and is tested in vitro. Hypaxidine performance is regulated by BMP6 / SMAD and IL-6 / STAT signaling pathways, where both BMP and IL-6 act through their respective receptors to promote increased hypaxidine performance. Casanovas et al.,PLOS Comp. Biol 10 (1): e1003421 (2014). Signaling pathways in vitro-agonists of recombinant BMP2 and IL-6-or BMP2 agonists alone are used to treat major and minor dual iPS cardiomyocytes to model IL-6 content (or signaling) Reduced clinical intervention. Control iPS cells were not treated with agonists. Cell mortality was measured under normal oxygen tension (normal oxygen) and also under conditions of simulated hypoxia followed by simulated reoxygenation (reperfusion). Figure 6A shows the results when cells were treated under normal oxygen content. Performance onlyTMPRSS6 rs855791 secondary dual gene ("736V secondary dual gene") iPS cardiomyocytes are not significantly affected by the elimination of IL-6 signaling ("ns"): Compared to the treatment with BMP2 + IL-6, when used When BMP2 treated cells, the percentage of cell mortality measured as a percentage of trypan blue positive cells did not decrease significantly. In contrast, when IL-6 signaling is eliminated, performanceTMPRSS6 rs855791 iPS cardiomyocytes, which are primarily dual genes, display statistically significantly lower cell death. Figure 6B shows the results when the cells undergo hypoxia followed by reoxygenation. Compared with normoxic conditions, hypoxia / reoxygenation is toxic to iPS cardiomyocytes, of which about 40% of the primary and secondary dual gene control cells are compared to about 20% of control cells killed under normoxic conditions Killed (compared to Figure 6A). In contrast to this increased background toxicity, the secondary dual iPS cardiomyocytes were not significantly affected by the elimination of IL-6 signaling: compared to the treatment with BMP2 + IL-6, the cells died when the cells were treated with BMP2 alone The rate does not decrease significantly. In contrast, when IL-6 signaling is eliminated, performanceTMPRSS6 rs855791 iPS cardiomyocytes, which are primarily dual genes, display statistically significantly lower cell death. These data enhance the inferences from the hoc analysis after the clinical trial data in Examples 1 and 2 that a reduction in IL-6 signaling effectively reduces performanceTMPRSS6 rs855791 is predominantly IL-6-mediated toxicity in cardiomyocytes of dual genes, but not in cardiomyocytes that exhibit only secondary dual genes. Without intending to be bound by theory, IL-6, which promotes increased toxicity in the principally dual iPS cardiomyocytes, may result from an IL-6-mediated increase in the expression of hypaxidine, followed by increased iron chelation in the cells, followed by Iron-mediated cytotoxicity. Patients with chronic kidney disease, such as those enrolled in the MIMICK study analyzed in Example 1, often suffer from impaired cardiac function, which is a major contributor to overall mortality. This second heart injury after the first chronic kidney disease is called type 4 cardiorenal syndrome (type 4 CRS). To test directly whether anti-IL-6 therapy is availableTMPRSS6 rs855791 is effective in CRS4 patients with at least one replica of the primary gene. As demonstrated by the data in Examples 1 and 3, we use genotypes similar toTMPRSS6 rs855791 is mainly a CRS4 model of human rats with homozygous genes. After 4 weeks of treatment, the treatment group-the group treated with anti-IL-6 antibody and the standard care ACE inhibitor therapy perindopril-demonstrated a statistically significantly increased ejection fraction compared to the isotype control Degree (Figure 8D) (p <0.001). The degree of anti-IL-6 measured after 4 weeks of treatment and the similar ejection fraction in the standard care group demonstrate that anti-IL-6 therapy has equivalent efficacy to ACE inhibitors. Figure 9 shows that anti-IL-6 therapy is also equivalent to ACE inhibitors in maintaining myocardial contractility. Figures 10A-10C show that anti-IL-6 therapy is also effective in reducing cardiac fibrosis. These data indicate that genotyping is similar to targetingTMPRSS6 rs855791 is an anti-IL-6 agent in vivo model of cardio-renal syndrome in vivo of human animals with homogeneous conjugation genes, which effectively reduces heart damage and restores function. Similarly, the data in Examples 2 and 3 show that reduced IL-6 content or IL-6 signaling can reduce heart failure and death in patients with acute coronary syndromes, but onlyTMPRSS6 rs855791 has the largest effect in their patients with at least one replica of the dual gene, and in their patients with elevated serum IL-6 content. Conduct research to determine genotypes similar toTMPRSS6 The role of rs855791 in anti-IL-6 therapy after acute myocardial infarction in human mice with homozygous dual genes. Figures 11A and 11B show data from an in vivo model in which genotypes are similar toTMPRSS6 rs855791 induces myocardial infarction in human mice whose primary dual genes are homozygous. The control group did not receive therapy. The experimental group was treated with anti-mouse IL-6 antibody. Figure 11A shows that treatment with anti-IL-6 provides a statistically significant increase in ejection fraction compared to the control. FIG. 11B shows that treatment with anti-IL-6 provided a statistically significant improvement in contractility measured as cardiac shortening fraction compared to control. These data indicate that the anti-IL-6 therapy given immediately after myocardial infarction improves genotype similar to that withTMPRSS6 rs855791 restores left ventricular function in rodents of human patients with primarily dual genes. In summary, experimental data indicate that therapeutic interventions that reduce IL-6 signaling will provide clinical benefits in patients with hepaxidine-mediated conditions, such as anemia or hepacitidine-mediated cytotoxicity, but only In havingTMPRSS6 rs855791 has the greatest effect in patients with at least one replica of the primary dual gene, among patients with elevated IL-6 content. Therefore, as described further below, in a first aspect, a method is provided for treating a hepaxidine-mediated disorder. The methods include administering a therapeutically effective amount of an IL-6 antagonist to a patient suffering from a hepaxidine-mediated condition, which patient has been determined to haveTMPRSS6 rs855791 At least one copy of the major dual gene at SNP. In a second aspect, there is provided a method for improving the treatment of a hepasidine-mediated disorder, the method comprising discontinuing administration of an IL-6 antagonist to a patient having a hepasidine-mediated disorder , Where the patient has been identified forTMPRSS6 The rs855791 minor dual gene is homozygous. Treatment is improved by discontinuing treatments that are inefficient, thereby reducing side effects and costs without losing therapeutic efficacy. In another aspect, a method is provided for treating an IL-6 mediated inflammatory condition in a patient without chronic inflammatory anemia, the method comprising administering to the patient a therapeutically effective amount of an IL-6 antagonist, the patient Has an IL-6-mediated inflammatory condition, does not have anemia, and has been identified as havingTMPRSS6 rs855791 is at least one copy of the primary dual gene. 5.2 Definitions Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which this invention belongs. As used herein, the following terms have the meanings ascribed to them below. "Hypaxidine "Means a polypeptide having an amino acid sequence identity of at least about 85% or greater than 85% of the amino acid sequence provided by NCBI accession number NP_066998 (" Hypaxidin proprotein ") or a biologically active fragment thereof. Exemplary biologics of hypaxidine include binding and reducing iron transport channel iron content, inhibiting iron transport, inhibiting intestinal iron absorption, and inhibiting iron release from macrophages and the liver. Exemplary hypasidine preprotein amino acid sequences are provided below:With reference to the sequence above, hypaxidine exists in various forms, including in the form of preprohormone (amino acids 25-84), prohormones (amino acids 25-84), and known as hypaxidine Mature forms of -25 (amino acid 60-84), hypaxidine-22 (amino acid 63-84), and hypaxidine-20 (amino acid 65-84). "Hypaxidine-mediated disorders "Is any condition in which hepaxadine appears to contribute to the cause of the condition or any of its symptoms. The contribution of hypaxidine to the cause is known, suspected, or inferred from an observation, which isTMPRSS6 rs855791 Patients with disorders whose secondary dual genes are homozygous, administration of IL-6 antagonistsTMPRSS6 The rs855791 SNP provides greater therapeutic benefit in patients with a disorder that has at least one copy of the primary dual gene. Hepaxidin-mediated disorders are described further below in Section 5.4.1. "Transmembrane protease serine 6 ( TMPRSS6 ) Peptide "Means a polypeptide or fragment thereof having an amino acid sequence identity of at least about 85% or greater than 85% and having serine protease activity, as provided by the NCBI accession number NP_001275929.TMPRSS6 Polypeptides, also known as interstitial protease-2 (MT2), break down hepcidin-regulating proteins and inhibit bone morphogenetic protein signaling. An example with alanine (736A) at position 736 is provided belowTMPRSS6 Amino acid sequence:Exemplary below has valine (736V) at position 736TMPRSS6 Amino acid sequence:" TMPRSS6 Nucleic acid molecule Meaning encodingTMPRSS6 Polynucleotide of a polypeptide (interstitial protease-2; MT2). ExemplaryTMPRSS6 Nucleic acid molecule sequences are provided under NCBI accession number NM_001289000. Provided below are nucleotides having a G ("G dual gene"; "primary dual gene") at nucleotide position 2321.TMPRSS6 Nucleic acid sequence: Provided below is a nucleotide having an A at nucleotide position 2321.TMPRSS6 Nucleic acid sequence: "Variant "Means a polynucleotide or polypeptide sequence that differs from a reference sequence by one or more nucleotides or one or more amino acids. ExemplaryTMPRSS6 Variant isTMPRSS6 (A736V), caused by SNP rs855791 (G → A). "Single nucleotide Polymorphism "or"SN "P" means a naturally occurring variant of a DNA sequence in which a single nucleotide in the genome differs between members of a biological species or between paired chromosomes in an individual. SNPs can be used as genetic markers for mutant dual genes. In one embodiment,TMPRSS6 The SNP is rs855791. "rs855791 Means humanTMPRSS6 Single Nucleotide Polymorphism (SNP) in genes, 2321G → A, inTMPRSS6 The catalytic region of the gene encoding mesoprotease-2 (MT2) caused substitution of alanine to valine (A736V). The highest frequency dual gene (main dual gene) in the human population is 2321G, encoding 736A. The duality gene (secondary duality gene) with the lowest frequency in the human population is 2321A, encoding 736V. "Profiled junction "It means that the chromosomal locus has two different dual genes. In one embodiment of the method described herein, heterozygosity refers to the following genotype: one of the dual genes has a gene encoding an amino acid having alanine at position 736 in the amino acid.TMPRSS6 Of peptidesTMPRSS6 Nucleic acid sequence (e.g. inTMPRSS6 Nucleic acid molecule has G or C at nucleotide position 2321) (rs855791 is a major dual gene), and the other dual gene has a gene encoding valinic acid at amino acid position 736TMPRSS6 Peptide variationTMPRSS6 Nucleic acid sequence (e.g. inTMPRSS6 Nucleic acid molecule has A or T at nucleotide position 2321 (rs855791 minor dual gene). "Homojunction "It means that the chromosomal locus has two identical dual genes. In certain embodiments of the methods described herein, homozygosity refers to the genotype in which two of the dual genes have a gene encoding an amino acid comprising alanine at position 736 of the amino acid.TMPRSS6 Of peptidesTMPRSS6 Nucleic acid sequence (e.g. inTMPRSS6 Nucleic acid molecule has G or C) at nucleotide position 2321 (rs855791 is the main dual gene for homology). In some embodiments, homozygosity refers to the genotype in which two of the dual genes have a gene encoding a valine containing amino acid at position 736 in the amino acid.TMPRSS6 Of peptidesTMPRSS6 Nucleic acid sequence (e.g. inTMPRSS6 Nucleic acid molecule has A or T) at nucleotide position 2321 (rs855791 secondary partner of homology). "Make sure the patient has TMPRSS6 rs855791 At least one copy of the major dual gene "Includes, but is not limited to, analysis to determine that the patient has at least one copy of the TMPRSS6 rs855791 major dual gene; ordering the analysis to determine that the patient has at least one copy of the TMPRSS6 rs855791 primary dual gene; provision for analysis to determine that the patient has TMPRSS6 rs855791 primary dual At least one copy of the gene; other directed or controlled analysis has been performed to determine that the patient has at least one copy of the TMPRSS6 rs855791 primary dual gene; andTMRSS6 Genotyping data or protein or nucleic acid sequence data to determine that the patient has at least one copy of the TMPRSS6 rs855791 primary dual gene. "Interleukin 6 (IL-6) "or"IL-6 Peptide "Means a polypeptide or fragment thereof having an amino acid sequence identity of at least about 85% or greater than 85% and having IL-6 biological activity with the amino acid sequence provided under NCBI accession number NP_000591. IL-6 is a pleiotropic cytokine with multiple biological functions. Exemplary IL-6 biological activities include immune stimulating and pro-inflammatory activities. Exemplary IL-6 amino acid sequences are provided below:"Interleukin 6 (IL-6) Nucleic acid "Means a polynucleotide encoding an interleukin 6 (IL-6) polypeptide. An exemplary interleukin 6 (IL-6) nucleic acid sequence is provided under NCBI Accession No. NM_000600. An exemplary sequence using NCBI deposit number NM_000600 is provided below. "Interleukin 6 Receptor (IL-6R) Complex "Means a protein comprising IL-6 receptor subunit α (IL-6Rα) and interleukin 6 signal transduction glycoprotein 130-also known as interleukin 6 receptor subunit β (IL-6Rβ)- Complex. "Interleukin 6 Receptor subunit α (IL-6Rα) Peptide "Means a polypeptide or fragment thereof having an amino acid sequence identity of at least about 85% or greater than 85% and having biological activity at the IL-6 receptor with an amino acid sequence provided under NCBI accession number NP_000556 or NP_852004. Exemplary IL-6Rα biological activities include binding to IL-6, binding to glycoprotein 130 (gp130), and regulating cell growth and differentiation. Exemplary IL-6R sequences are provided below:"Interleukin 6 Receptor subunit β (IL-6Rβ) Peptide "Means a polypeptide or fragment thereof having an amino acid sequence identity of at least about 85% or greater than 85% and having biological activity at the IL-6 receptor with an amino acid sequence provided under NCBI accession numbers NP_002175, NP_786943 or NP_001177910. Exemplary biological activities of IL-6Rβ include binding to IL-6Rα, IL-6 receptor signaling activity, and regulation of cell growth, differentiation, and performance of hypaxidine. Exemplary IL-6Rβ sequences are provided below: "IL-6 Antagonist "Means an agent capable of reducing the biological activity of IL-6. IL-6 antagonists include agents that reduce the amount of IL-6 polypeptide in serum, including agents that reduce the expression of IL-6 polypeptides or nucleic acids; agents that reduce the ability of IL-6 to bind to IL-6R; Expressive agents; and agents that reduce signal transduction by the IL-6R receptor when bound by IL-6. In a preferred embodiment, the IL-6 antagonist reduces the biological activity of IL-6 by at least about 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%, or even 100%. As further described in Section 5.9 below, IL-6 antagonists include IL-6 binding polypeptides, such as anti-IL-6 antibodies and antigen-binding fragments or derivatives thereof; IL-6R binding polypeptides, such as anti-IL-6R antibodies and antigens thereof Binding fragments or derivatives; and synthetic chemical molecules such as JAK1 and JAK3 inhibitors. "IL-6 antibody "or"anti- IL-6 antibody "Means an antibody that specifically binds to IL-6. Anti-IL-6 antibodies include single and multiple strains of antibodies specific for IL-6 and antigen-binding fragments or derivatives thereof. The IL-6 antibody is described in more detail in Section 5.9.1 below. "IL-6 Mediated inflammation "Means any condition where IL-6 is known or suspected to cause the disease or any of its symptoms. "Erythropoietin (EPO) "Means a polypeptide or fragment thereof having an amino acid sequence identity of at least about 85% or greater than 85% and having EPO biological activity with the amino acid sequence provided under NCBI accession number NP_000790. Exemplary EPO biological activities include binding to erythropoietin receptors and the proliferation and final differentiation of red blood cell precursor cells produced and / or increasing red blood cell production (red blood cell production). Exemplary EPO amino acid sequences are provided below:"Red blood cell stimulant (ESA) "It means a drug that stimulates the formation of red blood cells. ESA includes (but is not limited to) EPO; darbepoetin (Aranesp); epoetin beta (NeoRecormon); Delta Iber Epoetin delta (to Dynepo); epoetin omega (Epomax); epoetin zeta. "Erythropoietin "" Means an agent that increases the growth or proliferation of red blood cells or their progenitor cells (such as hematopoietic stem cells) and / or reduces the cell death of red blood cells or their progenitor cells. In various embodiments, the erythropoietin includes a erythrocyte stimulating agent, a HIF stabilizer, and iron supplementation. "C Reactive protein (CRP) Peptide "Means a polypeptide or fragment thereof that has at least about 85% or greater than 85% amino acid identity to the amino acid sequence provided by NCBI accession number NP_000558 and has complement activation activity. CRP content increases in response to inflammation. Exemplary CRP sequences are provided below:"Elixir "Means any compound or composition suitable for therapeutic administration, and explicitly includes chemical compounds; proteins, including antibodies or antigen-binding fragments thereof; peptides; and nucleic acid molecules. "individual "Means individual human or non-human mammals (including, but not limited to, cattle, horses, dogs, sheep, cats and rodents, including rodents and domestic rat species). "patient Is a human individual. As used herein, the term "treatment (treat / treating / treatment) "And the like refers to reducing or ameliorating the symptoms and / or signs or symptoms associated therewith, or slowing or stopping its progress. It should be understood that, although not excluded, treating a disorder or condition does not require complete elimination of the disorder, condition or symptoms associated therewith. "Before treatment "Means prior to the first administration of an IL-6 antagonist according to the method described herein. Treatment before treatment is not excluded and often includes treatment other than prior administration of an IL-6 antagonist. In the present invention, "contain (comprises, comprising) ",contain ( containing) ",have ",include (includes, including) "And its linguistic variations have the meaning given to them in U.S. patent law, allowing for the existence of components other than the narrator. "Biological sample "Means any tissue, cell, body fluid or other substance derived from an organism (such as a human individual). In some embodiments, the biological sample is serum or blood. "Angiotensin converting enzyme (ACE) Inhibitor "Means an agent that inhibits the biological function of angiotensin-converting enzyme to convert angiotensin I to angiotensin II. ACE inhibitors include, but are not limited to, quinapril, perindopril, ramipril, captopril, benazepril, trondopril (trandolapril), fosinopril, lisinopril, moexipril, and enalapril. In various embodiments, the ACE inhibitor is perindopril. 5.3 Other descriptive conventions Unless otherwise specified, antibody constant region residue numbering is based on the EU index in Kabat. The ranges provided herein are to be understood as shorthand for all values in the range, including the endpoints. For example, a range of 1 to 50 should be understood to include any value, combination of values, or subranges of a group consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 , 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50. Unless specifically stated or obvious from context, as used herein, the term "or" should be understood to include. Unless specifically stated or obvious from context, as used herein, the terms "a" and "an" should be singular or plural. Unless specifically stated or obvious from context, as used herein, the term "about" should be understood to be within normal tolerances in the technology, such as within 2 standard deviations of the mean. Approximately understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the stated value . Unless otherwise apparent from the context, all numerical values provided herein are modified by the term about. 5.4 Methods of Treating Hypaxidine-mediated Disorders In a first aspect, a method of treating a hippasidine-mediated disorder is provided. The methods include administering a therapeutically effective amount of an IL-6 antagonist to an individual (usually a human patient) with a hepaxidine-mediated condition, where the individual has been determined to haveTMPRSS6 rs855791 is at least one copy of the primary dual gene. In the first series of embodiments, it has previously been determined that the individual hasTMPRSS6 rs855791 is at least one copy of the primary dual gene. In another series of embodiments, the method further comprises determining that the individual hasTMPRSS6 rs855791 is an earlier step of at least one copy of the primary dual gene. In general, these methods definitely excludeTMPRSS6 rs855791 Minor dual genes are homozygous individuals. Generally, patients have elevated pre-treatment serum IL-6 levels. 5.4.1 Hypaxidine-mediated conditions 5.4.1.1 Chronic disease / chronic inflammatory anemia In various embodiments, the hypaxidine-mediated condition treated by the methods described herein is chronic disease anemia, also Called chronic inflammatory anemia. In various embodiments, the patient is male and has a pre-treatment hemoglobin (Hb) content of less than 14 g / dl. In some embodiments, the pre-treatment Hb content of male patients is 13.0-13.9 g / dl, 12.0-12.9 g / dl, 11.0-11.9 g / dl, 10.0-10.9 g / dl, or less than 10 g / dl. In various embodiments, the patient is a female and the Hb content is less than 12 g / dl before treatment. In some embodiments, the pre-treatment Hb content of a female patient is 11.0-11.9 g / dl, 10.0-10.9 g / dl, 9.0-9.9 g / dl, 8.0-8.9 g / dl, or less than 8 g / dl. In some of these embodiments, the patient has been treated with ESA before. In some embodiments, the patient has been treated with iron supplements. In some embodiments, the patient has been treated with an infusion of blood or red blood cell concentrate. In various embodiments, the patient is male and the pre-treatment hematocrit is less than 40%. In some embodiments, the pre-treatment hematocrit of a male patient is less than 39%, less than 38%, less than 37%, less than 36%, or less than 35%. In some embodiments, the pre-treatment hematocrit of a male patient is 39%, 38%, 37%, 36%, 35%, 34%, 33%, 32%, 31%, or 30%. In various embodiments, the patient is female and the pre-treatment blood volume ratio is less than 36%. In some embodiments, the pre-treatment hematocrit of a female patient is less than 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, or 26%. In certain embodiments, the pre-treatment hematocrit of a female patient is 35%, 34%, 33%, 32%, 31%, 30%, 29%, 28%, 27%, or 26%. In some of these embodiments, the patient has been treated with ESA. In some embodiments, the patient has been treated with iron supplements. In some embodiments, the patient has been treated with an infusion of blood or red blood cell concentrate. In some embodiments, the patient has been treated with ESA and has a normal pre-treatment Hb content and / or a normal pre-treatment blood volume ratio. In certain embodiments, the patient is male and has a pre-treatment hemoglobin (Hb) content of at least 14 g / dl, and / or a pre-treatment hematocrit of at least 40%. In certain embodiments, the patient is female and has an Hb content of at least 12 g / dl and / or a blood volume ratio of at least 36% before treatment. In a specific embodiment, the ESA is EPO. In a specific embodiment, the ESA is darbepoetin alfa. In some embodiments, the patient has been treated with iron supplementation and has a normal pre-treatment Hb content and / or a normal pre-treatment blood volume ratio. In certain embodiments, the patient is male and has a pre-treatment hemoglobin (Hb) content of at least 14 g / dl, and / or a pre-treatment hematocrit of at least 40%. In certain embodiments, the patient is female and has an Hb content of at least 12 g / dl and / or a blood volume ratio of at least 36% before treatment. In some embodiments, the patient has been treated with an infusion of whole blood or red blood cell concentrate and has a normal pre-treatment Hb content and / or a normal pre-treatment blood volume ratio. In certain embodiments, the patient is male and has a pre-treatment hemoglobin (Hb) content of at least 14 g / dl, and / or a pre-treatment hematocrit of at least 40%. In certain embodiments, the patient is female and has an Hb content of at least 12 g / dl and / or a blood volume ratio of at least 36% before treatment. In some embodiments, one dose of the IL-6 antagonist is administered on a time course and for a period of time sufficient to increase the patient's Hb content above the pre-treatment content. In some embodiments, one dose of the IL-6 antagonist is administered on a time schedule for a period of time sufficient to increase the patient's blood volume ratio above the pre-treatment level. In some embodiments, one dose of the IL-6 antagonist is administered on a time schedule for a period of time sufficient to increase both the Hb content and the blood volume ratio above the pre-treatment content. In some embodiments, one dose of the IL-6 antagonist is administered on a time schedule and for a period of time sufficient to reduce the patient's ESA dose below the pre-treatment level without reducing the patient's Hb content. In some embodiments, one dose of the IL-6 antagonist is administered on a time schedule and for a period of time sufficient to reduce the patient's ESA dose below the pre-treatment level without reducing the patient's blood volume ratio. In some embodiments, one dose of the IL-6 antagonist is administered on a time schedule and for a period of time sufficient to reduce the patient's ESA dose without reducing the patient's Hb content and blood volume ratio. In some embodiments, one dose of the IL-6 antagonist is administered on a time schedule and for a period of time sufficient to reduce the patient's ESA dose compared to the pre-treatment ESA dose by at least 10%. In certain embodiments, a dose of an IL-6 antagonist is administered on a schedule that is sufficient to reduce the patient's ESA dose by at least 20%, 30%, 40%, or 50% compared to the pre-treatment ESA dose. Time period. In a particular embodiment, one dose of the IL-6 antagonist is administered on a time schedule and for a period of time sufficient to reduce the patient's ESA dose compared to the pre-treatment ESA dose by at least 60% or even at least 75%. In some embodiments, one dose of the IL-6 antagonist is administered over a period of time and for a period of time sufficient to reverse functional iron deficiency. 5.4.1.1.1 Chronic kidney disease In various embodiments, the chronic disease is chronic kidney disease (CKD). In some embodiments, the patient has KDOQI stage 1 chronic kidney disease. In certain embodiments, the patient has KDOQI stage 2 chronic kidney disease, KDOQI stage 3 chronic kidney disease, KDOQI stage 4 chronic kidney disease, or KDOQI stage 5 chronic kidney disease. In some embodiments, the patient has a cardio-renal syndrome (CRS). In certain embodiments, the patient has type 4 CRS. In some embodiments, the patient has been treated with dialysis. In some embodiments, one dose of the IL-6 antagonist is administered on a time course and for a period of time sufficient to reduce cardiovascular (CV) mortality compared to an age-matched and disease-matched historical cohort. 5.4.1.1.2 Chronic inflammatory disease In various embodiments, the chronic disease is a chronic inflammatory disease. In some embodiments, the chronic inflammatory disease is rheumatoid arthritis (RA). In a specific embodiment, the patient's pre-treatment DAS28 score is greater than 5.1. In some embodiments, the patient's pre-treatment DAS28 score is 3.2 to 5.1. In some embodiments, the patient's pre-treatment DAS28 score is less than 2.6. In various embodiments, the patient's pre-treatment RA is severely active. In some embodiments, the patient's pre-treatment RA is moderately active. In certain embodiments, the patient has been treated with methotrexate. In some embodiments, methotrexate is discontinued when treatment with an IL-6 antagonist is initiated. In some embodiments, when treatment with an IL-6 antagonist is initiated, treatment with methotrexate is continued. In certain embodiments, the patient has been treated with an anti-TNFα agent. In a particular embodiment, the anti-TNFa agent is selected from the group consisting of etanercept, adalimumab, infliximab, cetuzumab, and golimumab. In a particular embodiment, the anti-TNFa agent is discontinued when treatment with an IL-6 antagonist is initiated. In certain embodiments, the patient has been treated with an IL-I receptor antagonist. In a specific embodiment, the IL-1 receptor antagonist is anakinra. In a specific embodiment, the IL-1 receptor antagonist is discontinued when treatment with the IL-6 antagonist is initiated. In certain embodiments, the patient has been treated with abatacept. In a particular embodiment, abascept is discontinued when treatment with an IL-6 antagonist is initiated. In certain embodiments, the patient has been treated with an IL-6 antagonist, and the method further comprises continuing toTMPRSS6 rs855791 only IL-6 antagonists were administered to their patients in at least one replica of the primary dual gene. In a specific embodiment, the IL-6 antagonist is tocilizumab. In a specific embodiment, the IL-6 antagonist is tofacitinib. In various embodiments, the chronic inflammatory disease is selected from the group consisting of juvenile idiopathic arthritis, ankylosing spondylitis, plaque psoriasis, psoriasis arthritis, inflammatory bowel disease, Crohn's disease, and ulcers Colitis. 5.4.1.1.3 Cancer In various embodiments, the chronic disease is cancer. In some embodiments, the cancer is selected from the group consisting of: solid tumors, small cell lung cancer, non-small cell lung cancer, blood cancer, multiple myeloma, leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML) ), Lymphoma and Hodgkin's lymphoma. 5.4.1.1.4 Chronic infection In various embodiments, the chronic disease is a chronic infection. 5.4.1.1.5 Congestive heart failure In various embodiments, the chronic disease is congestive heart failure (CHF). 5.4.1.2 Iron-refractory iron-deficiency anemia (IRIDA) In various embodiments, the hypaxidine-mediated condition is iron-refractory iron-deficiency anemia (IRIDA). 5.4.1.3 Anemia associated with hepatic adenoma-derived hepatic adenomas In various embodiments, a hepacilidine-mediated condition is anemia associated with hepatic adenoma-produced liver adenomas. 5.4.1.4 Acute coronary syndromes The data presented in Examples 2, 3, and 5 below show that IL-6 antagonists are effective in reducing the risk of heart failure and death after acute myocardial infarction, and that they increase heart function and reduce fiber Effective. Thus, in various embodiments, the hypoxidazole-mediated condition is acute coronary syndrome. In certain embodiments, the patient has suffered a myocardial infarction within 60 days before the first administration of an IL-6 antagonist. In a specific embodiment, the patient has suffered a myocardial infarction within 30, 14, 7, 48, or 24 hours before the first administration of the IL-6 antagonist. In some embodiments, one dose of the IL-6 antagonist is administered on a time course and for a period of time sufficient to improve myocardial contractility compared to before treatment. In certain embodiments, one dose of the IL-6 antagonist is administered over a period of time and for a period of time sufficient to increase the cardiac ejection fraction compared to that before treatment. In certain embodiments, one dose of the IL-6 antagonist is administered over a period of time and for a period of time sufficient to reduce cardiac fibrosis compared to before treatment. 5.4.1.5 Castleman's Disease In various embodiments, the disease that is mediated by Hypaxidine is Castleman's Disease. 5.5 Improved methods for the treatment of hippasidine-mediated disorders In another aspect, methods are provided to improve the treatment of hippasadine-mediated disorders by discontinuing them as ineffective therapy, thereby Reduces side effects and costs when treatment efficacy is lost. The methods include discontinuing the administration of an IL-6 antagonist to a patient with a hepaxidine-mediated condition, where the patient has been determined to beTMPRSS6 The rs855791 minor dual gene is homozygous. In a series of embodiments, the patient has previously been determined toTMPRSS6 The rs855791 minor dual gene is homozygous. In another series of embodiments, the method further includes determining that the patient isTMPRSS6 The rs855791 minor dual gene is an earlier step for homozygosity. In a typical embodiment, the patient has an elevated pre-treatment serum IL-6 content. In various embodiments, the patient has an elevated pre-treatment serum CRP content. In various embodiments, the patient has a hepaxidine-mediated disorder selected from the group of those disorders described in Section 5.4.1 above. In certain embodiments, the patient has chronic disease anemia. 5.6 Methods for the Treatment of IL-6-Mediated Inflammatory ConditionsThe data presented in Examples 2, 3, and 5 indicate that prior to treatmentTMPRSS6 IL-6 antagonists provide therapeutic benefit in individuals with at least one replica of a major dual gene, or even in the absence of anemia. Therefore, in another aspect, methods are provided to treat IL-6-mediated inflammatory conditions in patients without chronic inflammatory anemia. The methods include administering a therapeutically effective amount of an IL-6 antagonist to an individual, typically a human patient, with an IL-6 mediated inflammatory condition, wherein the patient does not suffer from anemia, and wherein the individual has been determined to haveTMPRSS6 rs855791 is at least one copy of the primary dual gene. In the first series of embodiments, it has previously been determined that the individual hasTMPRSS6 rs855791 is at least one copy of the primary dual gene. In another series of embodiments, the method further comprises determining that the individual hasTMPRSS6 rs855791 is an earlier step of at least one copy of the primary dual gene. Usually, the method definitely excludesTMPRSS6 rs855791 Minor dual genes are homozygous individuals. Generally, patients have elevated pre-treatment serum IL-6 levels. In some embodiments, the IL-6 mediated disorder is rheumatoid arthritis (RA). In a specific embodiment, the patient's pre-treatment DAS28 score is greater than 5.1. In some embodiments, the patient's pre-treatment DAS28 score is 3.2 to 5.1. In some embodiments, the patient's pre-treatment DAS28 score is less than 2.6. In various embodiments, the patient's pre-treatment RA is severely active. In some embodiments, the patient's pre-treatment RA is moderately active. In certain embodiments, the patient has been treated with methotrexate. In some embodiments, methotrexate is discontinued when treatment with an IL-6 antagonist is initiated. In some embodiments, methotrexate is continued when treatment with an IL-6 antagonist is initiated. In certain embodiments, the patient has been treated with an anti-TNFα agent. In a particular embodiment, the anti-TNFa agent is selected from the group consisting of etanercept, adalimumab, infliximab, cetuzumab, and golimumab. In a particular embodiment, the anti-TNFa agent is discontinued when treatment with an IL-6 antagonist is initiated. In certain embodiments, the patient has been treated with an IL-I receptor antagonist. In a specific embodiment, the IL-1 receptor antagonist is anakinra. In a specific embodiment, the IL-1 receptor antagonist is discontinued when treatment with the IL-6 antagonist is initiated. In certain embodiments, the patient has been treated with abatacept. In a particular embodiment, abascept is discontinued when treatment with an IL-6 antagonist is initiated. In various embodiments, the IL-6 mediated disorder is selected from the group consisting of juvenile idiopathic arthritis, ankylosing spondylitis, plaque psoriasis, psoriasis arthritis, inflammatory bowel disease, Crohn 'S disease and ulcerative colitis. 5.7 Pre-treatment serum IL-6 and CRP levels In a typical embodiment of the method described herein, the patient has an elevated pre-treatment serum IL-6 level. In some embodiments, the patient's pre-treatment serum IL-6 content is greater than 2.5 pg / ml. In various embodiments, the patient's pre-treatment serum IL-6 content is greater than 5 pg / ml, greater than 7.5 pg / ml, greater than 10 pg / ml, greater than 12.5 pg / ml, or greater than 15 pg / ml. In some embodiments, one dose of the IL-6 antagonist is administered on a time schedule for a period of time sufficient to reduce the patient's serum IL-6 content below the pre-treatment level. In certain embodiments, a dose of an IL-6 antagonist is administered on a schedule that is sufficient to reduce the patient's serum IL-6 content by at least 10%, 20%, 30%, 40% compared to the pre-treatment level. % Or 50% time period. In various embodiments, the patient has an elevated pre-treatment C-reactive protein (CRP) content. In some embodiments, the patient's pre-treatment CRP content is greater than 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 4.5 mg / ml, or 5 mg / ml. In some embodiments, the patient's pre-treatment CRP content is greater than 7.5 mg / ml, 10 mg / ml, 12.5 mg / ml, or 15 mg / ml. In some embodiments, one dose of the IL-6 antagonist is administered on a time course and for a period of time sufficient to reduce the patient's CRP content below the pre-treatment level. In certain embodiments, a dose of an IL-6 antagonist is administered on a schedule that is sufficient to reduce the patient's CRP content by at least 10%, 20%, 30%, 40%, or 50% compared to the pre-treatment level. % Time period. 5.8TMPRSS6 rs855791 Genotyping The methods described herein includeTMPRSS6 rs855791 administers a therapeutically effective amount of an IL-6 antagonist to an individual who has at least one duplicate of the gene. Preferably, the identification of two dual genes corresponding to related genes, thus allowing identification and differentiation of the following patients:TMPRSS6 rs855791 The major dual genes are homozygous, targeting the major and minorTMPRSS6 rs855791 dual genes are heterozygous, and targetedTMPRSS6 The rs855791 minor dual gene is homozygous. Use standard techniques to determine SNP rs855791 (2321G → A) atTMPRSS6 Deficiency (primary dual gene) or presence (secondary dual gene) in genes. Generally, PCR is used to amplify a biological sample obtained from a patient. In some embodiments, the use of real-time PCR (RT-PCR) simultaneously detects the absence or presence of polymorphism under amplification. In certain embodiments, RT-PCR analysis uses 5 'nucleases (TaqMan® probes), molecular beacons, and / or FRET hybridization probes.Summarized in Espy et al.,Clin. Microbiol. Rev January 2006; 19 (1): 165-256, which is incorporated herein by reference in its entirety. In a typical embodiment, a commercially available analysis is used. In selected embodiments, the commercially available analysis is selected from the group consisting of: TaqMan ™ SNP genotyping analysis (ThermoFisher); PCR SNP genotyping analysis (Qiagen); Novalele genotyping analysis (Canon); And SNP Type ™ analysis (formerly SNPtype) (Fluidigm). In some embodiments, hybridization with probes specific for SNP rs855791, restriction endonuclease digestion, nucleic acid sequencing, primer extension, microarray or gene chip analysis, mass spectrometry analysis, and / Or DNase protection analysis to detect the absence or presence of polymorphism. In some embodiments, dual gene variants are read by sequencing. In some embodiments, Sanger sequencing is used. In some embodiments, one of a variety of next-generation sequencing technologies is used, including, for example, sequencing technologies selected from the group consisting of: microarray sequencing, Solexa sequencing (Illumina), ion rapids (Life Technologies) , SOliD (Applied Biosystems), pyrophosphate sequencing, single molecule instant sequencing (Pacific Bio), nanopore sequencing, and tunneling current sequencing. 5.9 IL-6 antagonists IL-6 antagonists used in the methods described herein can reduce the biological activity of IL-6. 5.9.1 Anti-IL-6 antibodies In various embodiments, the IL-6 antagonist is an anti-IL-6 antibody or an antigen-binding fragment or derivative thereof. In some embodiments, the IL-6 antagonist is a full-length anti-IL-6 monoclonal antibody. In a specific embodiment, the full-length monoclonal antibody is an IgG antibody. In certain embodiments, the full-length monoclonal antibody is an IgG1, IgG2, IgG3, or IgG4 antibody. In some embodiments, the IL-6 antagonist is a multiple strain composition comprising a plurality of substances of a full-length anti-IL-6 antibody, each of the plurality of species having a unique CDR. In some embodiments, the IL-6 antagonist is an antibody fragment selected from the group consisting of Fab, Fab 'and F (ab') 2 fragments. In some embodiments, the IL-6 antagonist is a scFv, a disulfide-linked Fv (dsFv), or a single-domain antibody, such as a VHH single-domain nanobody derived from camel. In some embodiments, the IL-6 antagonist is an immunoconjugate or fusion comprising an IL-6 antigen-binding fragment. In some embodiments, the antibody is bispecific or multispecific, wherein at least one of the antigen-binding portions has specificity for IL-6. In some embodiments, the antibody is fully human. In some embodiments, the antibody is humanized. In some embodiments, the antibodies are chimeric and have non-human V regions and human C regions. In some embodiments, the antibody is murine. In typical embodiments, the anti-IL-6 antibody has a K of less than 100 nM for human IL-6 bindingD . In some embodiments, the binding of the anti-IL-6 antibody to human IL-6 has a K of less than 75 nM, 50 nM, 25 nM, 20 nM, 15 nM, or 10 nMD . In specific embodiments, the binding of the anti-IL-6 antibody to human IL-6 has a K of less than 5 nM, 4 nM, 3 nM, or 2 nMD . In selected embodiments, the binding of anti-IL-6 antibodies to human IL-6 has a K of less than 1 nM, 750 pM, or 500 pMD . In specific embodiments, the binding of anti-IL-6 antibodies to human IL-6 has a K of not greater than 500 pM, 400 pM, 300 pM, 200 pM, or 100 pM.D . In a typical embodiment, an anti-IL-6 antibody neutralizes the biological activity of IL-6. In some embodiments, the neutralizing antibody prevents IL-6 from binding to the IL-6 receptor. In a typical embodiment, the anti-IL-6 antibody has an elimination half-life of at least 7 days after intravenous administration. In certain embodiments, the elimination half-life of the anti-IL-6 antibody is at least 14 days, at least 21 days, or at least 30 days. In some embodiments, the anti-IL-6 antibody has a human IgG constant region with at least one amino acid substitution (extended serum half-life) compared to an unsubstituted human IgG constant domain. In certain embodiments, the IgG constant domain comprises substitutions at residues 252, 254, and 256, wherein the amino acid substitution at amino acid residue 252 is substituted with tyrosine and the amino acid residue 254 The amino acid substitution was substituted with threonine and the amino acid substitution at 256 amino acid residues was substituted with glutamic acid ("YTE"). See U.S. Patent No. 7,083,784, which is incorporated herein by reference in its entirety. In certain extended half-life embodiments, the IgG constant domain comprises a substitution selected from T250Q / M428L (Hinton et al.,J. Immunology 176: 346-356 (2006)); N434A (Yeung et al.,J. Immunology 182: 7663-7671 (2009)); or T307A / E380A / N434A (Petkova et al.,International Immunology , 18: 1759-1769 (2006)). In some embodiments, the elimination half-life of the anti-IL-6 antibody is increased by utilizing the FcRN binding properties of human serum albumin. In certain embodiments, the antibody binds to albumin (Smith et al.,Bioconjug. Chem ., 12: 750-756 (2001)). In some embodiments, an anti-IL-6 antibody is fused to a bacterial albumin binding domain (Stork et al.,Prot. Eng. Design Science 20: 569-76 (2007)). In some embodiments, the anti-IL-6 antibody is fused to an albumin binding peptide (Nguygen et al.,Prot Eng Design Sel 19: 291-297 (2006)). In some embodiments, the anti-IL antibodies are bispecific, one of which is specific for IL-6, and one of which is specific for human serum albumin (Ablynx, WO 2006/122825 (bispecific nanobodies)). In some embodiments, the elimination half-life of the anti-IL-6 antibody is increased by: PEGylation (Melmed et al.,Nature Reviews Drug Discovery 7: 641-642 (2008)); HPMA copolymer binding (Lu et al.,Nature Biotechnology 17: 1101-1104 (1999)); polyglucose binding (Nuclear Medicine Communications , 16: 362-369 (1995)); in combination with high amino acid polymers (HAP; HAP) (Schlapschy et al.,Prot Eng Design Sel 20: 273-284 (2007)); or polysialylation (Constantinou et al.,Bioconjug. Chem 20: 924-931 (2009)). 5.9.1.1.1 MED5117 and derivatives In certain embodiments, the anti-IL-6 antibody or antigen-binding portion thereof comprises all six CDRs of MEDI5117. In a specific embodiment, the antibody or antigen-binding portion thereof comprises a MEDI5117 heavy chain V region and a light chain V region. In a specific embodiment, the antibody is a full-length MEDI5117 antibody. The MEDI5117 antibody is described in WO 2010/088444 and US 2012/0034212, whose disclosures are incorporated herein by reference in their entirety. MEDI5117 antibody has the following CDRs and heavy and light chain sequences: MEDI5117 VH CDR1MEDI5117 VH CDR2MEDI5117 VH CDR3MEDI5117 VL CDR1MEDI5117 VL CDR2MEDI5117 VL CDR3MEDI5117 heavy chainMEDI5117 light chainIn various embodiments, the anti-IL-6 antibody is a derivative of MED5117. In some embodiments, the MED5117 derivative includes one or more amino acid substitutions in the MED5117 heavy and / or light chain V region. In certain embodiments, relative to the initial V of the MEDI5117 anti-IL-6 antibodyH And / or VL Derivatives contain less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less At 4 amino acid substitutions, less than 3 amino acid substitutions, less than 2 amino acid substitutions, or 1 amino acid substitution, while retaining specificity for human IL-6. In certain embodiments, the MED5117 derivative comprises at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% of the amino acid sequence of the VH and VL domains of MEDI5117. , At least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical amino acid sequences. The BLAST algorithm was used to determine the percent sequence identity using preset parameters. In certain embodiments, the MED5117 derivative comprises the following amino acid sequence: wherein the CDRs comprise at least 45%, at least 50%, at least 55%, at least 60%, at least 65% of the amino acid sequences of the respective CDRs of MEDI5117 , At least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical amino acid sequences. The BLAST algorithm was used to determine the percent sequence identity using preset parameters. In some embodiments, VH And / or VL CDR derivatives contain conservative amino acid substitutions at one or more predicted non-essential amino acid residues (ie, amino acid residues that are not essential for the antibody to specifically bind to human IL-6). 5.9.1.1.2 Other anti-IL-6 antibodies In various embodiments, the anti-IL-6 antibody comprises six CDRs from an antibody selected from the group consisting of: stuximab, grilimuzumab, Silukumab, Clarazizumab, Onochumab, Elsizumab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), ARGX-109 (ArGEN -X), FM101 (Femta Pharmaceuticals, Lonza) and ALD518 / BMS-945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb). In certain embodiments, the anti-IL-6 antibody comprises a heavy chain V region and a light chain V region from an antibody selected from the group consisting of: steruximab, grelimizumab, silukumab Antibody, clazacizumab, onochomab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), ARGX-109 (ArGEN-X), FM101 (Femta Pharmaceuticals, Lonza ) And ALD518 / BMS-945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb). In a specific embodiment, the anti-IL-6 antibody is an antibody selected from the group consisting of: stuximab, grelimizumab, siluzumab, clazazumab, onochizumab Antibody, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), ARGX-109 (ArGEN-X), FM101 (Femta Pharmaceuticals, Lonza), and ALD518 / BMS-945429 (Alder Biopharmaceuticals, Bristol) -Myers Squibb). In some embodiments, the anti-IL-6 antibody comprises six CDRs from an antibody selected from their antibodies described in each of: US 2016/0168243, US 2016/0130340, US 2015/0337036, US 2015 / 0203574, US 2015/0140011, US 2015/0125468, US 2014/0302058, US 2014/0141013, US 2013/0280266, US 2013/0017575, US 2010/0215654, US 2008/0075726, US Patent No. 5,856,135, US 2006 / 0240012, US 2006/0257407 or US Patent No. 7291721, the disclosure of which is incorporated herein by reference in its entirety. 5.9.2 Anti-IL-6 receptor antibodies In various embodiments, the IL-6 antagonist is an anti-IL-6 receptor antibody or an antigen-binding fragment or derivative thereof. In some embodiments, the IL-6 antagonist is a full-length anti-IL-6 receptor monoclonal antibody. In a specific embodiment, the full-length monoclonal antibody is an IgG antibody. In certain embodiments, the full-length monoclonal antibody is an IgG1, IgG2, IgG3, or IgG4 antibody. In some embodiments, the IL-6 antagonist is a multiple strain composition comprising a plurality of substances of a full-length anti-IL-6 receptor antibody, each of the plurality of species having a unique CDR. In some embodiments, the IL-6 antagonist is an antibody fragment selected from a Fab and a Fab 'fragment. In some embodiments, the IL-6 antagonist is a scFv, single domain antibody, including a camel derived VHH single domain nanobody. In some embodiments, the antibody is bispecific or multispecific, wherein at least one of the antigen-binding portions has specificity for IL-6R. In some embodiments, the antibody is fully human. In some embodiments, the antibody is humanized. In some embodiments, the antibodies are chimeric and have non-human V regions and human C regions. In some embodiments, the antibody is murine. In typical embodiments, the anti-IL-6 receptor antibody has a K of less than 100 nM for human IL-6R bindingD . In some embodiments, the binding of an anti-IL-6R antibody to human IL-6R has a K of less than 75 nM, 50 nM, 25 nM, 20 nM, 15 nM, or 10 nMD . In specific embodiments, the anti-IL-6 receptor antibody has a K of less than 5 nM, 4 nM, 3 nM, or 2 nM for human IL-6R binding.D . In selected embodiments, the anti-IL-6 receptor antibody has a K of less than 1 nM, 750 pM, or 500 pM for human IL-6R bindingD . In specific embodiments, the binding of the anti-IL-6 receptor antibody to human IL-6R has a K of not greater than 500 pM, 400 pM, 300 pM, 200 pM, or 100 pMD . In typical embodiments, anti-IL-6R reduces the biological activity of IL-6. In a typical embodiment, the anti-IL-6R antibody has an elimination half-life of at least 7 days after intravenous administration. In certain embodiments, the elimination half-life of the anti-IL-6R antibody is at least 14 days, at least 21 days, or at least 30 days. In some embodiments, the anti-IL-6R antibody has a human IgG constant region with at least one amino acid substitution (extended serum half-life) compared to an unsubstituted human IgG constant domain. In certain embodiments, the IgG constant domain comprises substitutions at residues 252, 254, and 256, wherein the amino acid substitution at amino acid residue 252 is substituted with tyrosine and the amino acid residue 254 The amino acid substitution was substituted with threonine and the amino acid substitution at 256 amino acid residues was substituted with glutamic acid ("YTE"). See U.S. Patent No. 7,083,784, which is incorporated herein by reference in its entirety. In certain extended half-life embodiments, the IgG constant domain comprises a substitution selected from: T250Q / M428L (Hinton et al., J. Immunology 176: 346-356 (2006)); N434A (Yeung et al., J. Immunology 182 : 7663-7671 (2009)); or T307A / E380A / N434A (Petkova et al., International Immunology, 18: 1759-1769 (2006)). In some embodiments, the elimination half-life of anti-IL-6R antibodies is increased by utilizing the FcRN binding properties of human serum albumin. In certain embodiments, the antibody binds to albumin (Smith et al., Bioconjug. Chem., 12: 750-756 (2001)). In some embodiments, an anti-IL-6R antibody is fused to a bacterial albumin binding domain (Stork et al., Prot. Eng. Design Science 20: 569-76 (2007)). In some embodiments, the anti-IL-6 antibody is fused to an albumin binding peptide (Nguygen et al., Prot Eng Design Sel 19: 291-297 (2006)). In some embodiments, the anti-IL antibodies are bispecific, one of which is specific for IL-6R, and one of which is specific for human serum albumin (Ablynx, WO 2006/122825 (bispecific nanobodies)). In some embodiments, the elimination half-life of anti-IL-6R antibodies is increased by: PEGylation (Melmed et al., Nature Reviews Drug Discovery 7: 641-642 (2008)); HPMA copolymer binding (Lu et al., Nature Biotechnology 17: 1101-1104 (1999)); polyglucose binding (Nuclear Medicine Communications, 16: 362-369 (1995)); binding to high amino acid polymers (HAP; HAP) (Schlapschy et al., Prot Eng Design Sel 20: 273-284 (2007)); or polysialylation (Constantinou et al., Bioconjug. Chem. 20: 924-931 (2009)). In certain embodiments, the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of tocilizumab. In a specific embodiment, the antibody or antigen-binding portion thereof comprises a tocilizumab heavy chain V region and a light chain V region. In a specific embodiment, the antibody is a full-length tocilizumab antibody. In certain embodiments, the anti-IL-6R antibody or antigen-binding portion thereof comprises all six CDRs of sarilumab. In a particular embodiment, the antibody or antigen-binding portion thereof comprises a Vari region of a heavy chain and a light chain of a Salivumab antibody. In a specific embodiment, the antibody is a full-length salivumab antibody. In certain embodiments, the anti-IL-6R antibody or antigen-binding portion thereof comprises all six of the following CDRs: VX30 (Vaccinex), ARGX-109 (arGEN-X), FM101 (Formatech), SA237 (Roche), NI -1201 (NovImmune) or an antibody as described in US 2012/0225060. In certain embodiments, the anti-IL-6R antibody or antigen-binding portion thereof is a single domain antibody. In a specific embodiment, the single domain antibody is a camel VHH single domain antibody. In a specific embodiment, the antibody is fabolizumab (ALX-0061) (Ablynx NV). 5.9.3 Anti-IL-6: IL-6R complex antibody In various embodiments, the IL-6 antagonist is an antibody specific for a complex of IL-6 and IL-6R. In certain embodiments, the antibodies have six CDRs selected from antibodies to their antibodies described in US 2011/0002936, which is incorporated herein by reference in its entirety. 5.9.4 JAK and STAT inhibitors IL-6 is known to transmit via the JAK-STAT pathway. In various embodiments, the IL-6 antagonist is an inhibitor of the JAK signaling pathway. In some embodiments, the JAK inhibitor is a JAK1-specific inhibitor. In some embodiments, the JAK inhibitor is a JAK3-specific inhibitor. In some embodiments, the JAK inhibitor is a pan-JAK inhibitor. In certain embodiments, the JAK inhibitor is selected from the group consisting of tofacitinib (Xeljanz), desentinib, luzotinib, yupatinib, barretinib, figotinib , Ritutinib, paritinib, picofinib, INCB-039110, ABT-494, INCB-047986 and AC-410. In various embodiments, the IL-6 antagonist is a STAT3 inhibitor. In a specific embodiment, the inhibitor is AZD9150 (AstraZeneca, Isis Pharmaceuticals), STAT3 antisense molecule. 5.9.5 Additional IL-6 Antagonists In various embodiments, the IL-6 antagonist is an antagonist peptide. In certain embodiments, the IL-6 antagonist is C326 (Avidia's IL-6 inhibitor, also known as AMG220) or FE301, a recombinant protein inhibitor of IL-6 (Ferring International Center SA, Conaris Research Institute AG ). In some embodiments, the anti-IL-6 antagonist comprises soluble gp130, FE301 (Conaris / Ferring). 5.10 Dosing regimen 5.10.1 Antibodies, antigen-binding fragments, peptides In typical embodiments, antibodies, antigen-binding fragments, and peptide IL-6 antagonists are administered parenterally. In some parenteral embodiments, the IL-6 antagonist is administered intravenously. In certain intravenous embodiments, the IL-6 antagonist is administered as a bolus. In certain intravenous embodiments, the IL-6 antagonist is administered as an infusion. In certain intravenous embodiments, the IL-6 antagonist is administered as a bolus, followed by an infusion. In some parenteral embodiments, the IL-6 antagonist is administered subcutaneously. In various embodiments, the antibody, antigen-binding fragment, or peptide IL-6 antagonist is administered in a dose (uniform dose) that is independent of the weight or surface area of the patient. In some embodiments, the uniform intravenous dose is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In some embodiments, the uniform intravenous dose is 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some embodiments, the uniform intravenous dose is 25 mg, 30 mg, 40 mg, or 50 mg. In some embodiments, the uniform intravenous dose is 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. In some embodiments, the uniform intravenous dose is 1-10 mg, 10-15 mg, 15-20 mg, 20-30 mg, 30-40 mg, or 40-50 mg. In some embodiments, the uniform intravenous dose is 1-40 mg or 50-100 mg. In some embodiments, the uniform subcutaneous dose is 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. In some embodiments, the uniform subcutaneous dose is 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg. In some embodiments, the uniform subcutaneous dose is 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg. In some embodiments, the uniform subcutaneous dose is 10-100 mg, 100-200 mg, or 200-250 mg. In some embodiments, the uniform subcutaneous dose is 10-20 mg, 20-30 mg, 30-40 mg, 40-50 mg, 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg or 90-100 mg. In some embodiments, the uniform subcutaneous dose is 100-125 mg, 125-150 mg, 150 -175 mg, 175-200 mg, or 200-250 mg. In various embodiments, the antibody, antigen-binding fragment or peptide IL-6 antagonist is administered at a dose based on the weight of the patient. In some embodiments, the antagonist is at 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg or 1.0 mg / kg intravenously. In some embodiments, the antagonist is at a dose of 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, or 5 mg / kg Vote for. In some embodiments, subcutaneous weight-based doses are 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg or 1.0 mg / kg. In some embodiments, the antagonist is at a dose of 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, or 5 mg / kg Vote for. In various intravenous embodiments, the IL-6 antagonist is administered every 7 days, once every 14 days, once every 21 days, once every 28 days, or once a month. In various subcutaneous embodiments, the IL-6 antagonist is administered every 14 days, once every 28 days, once a month, once every two months (every other month) or every three months Give it once. In certain preferred embodiments, the IL-6 antagonist is a MEDI5117 antibody. In various embodiments, MEDI5117 is administered IV once a week at a uniform dose of 1-30 mg. In certain embodiments, the MEDI5117 antibody is administered IV uniformly once a week at a uniform dose of 1, 2, 3, 4, 5, 7.5, 10, 15, 20, 25, or 30 mg. In some embodiments, the MEDI5117 antibody is administered at a uniform dose of 25-250 mg once a month to s.c. once every three months. In specific embodiments, MEDI5117 is at a dose of 30 mg, 45 mg, 60 mg, 75 mg, 100 mg, 120 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 240 mg, or 250 mg per month Sc, once every two months or once every 3 months. In some embodiments, the IL-6 antagonist is tocilizumab. In various embodiments, for patients ≥100 kg, tocilizumab is administered s.c. once a week at a starting dose of 162 mg. In some embodiments, based on the clinical response, tocilizumab is administered intravenously at a dose of 4 mg / kg once every 4 weeks and then raised to 8 mg / kg once every 4 weeks. 5.10.2 JAK and STAT Inhibitors In typical embodiments, small molecule JAK inhibitors and STAT inhibitors are administered orally. In various embodiments, the inhibitor is administered at an oral dose of 1-10 mg, 10-20 mg, 20-30 mg, 30-40 mg, or 40-50 mg once or twice a day. In some embodiments, the inhibitor is administered once or twice a day at a dose of 50-60 mg, 60-70 mg, 70-80 mg, 80-90 mg, or 90-100 mg. In some embodiments, the inhibitor is administered PO once or twice a day at a dose of 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg. In some embodiments, the inhibitor is administered at a 75 mg dose of PO QD or BID and at a 100 mg dose of PO QD or BID. In certain embodiments, the JAK inhibitor is tofacitinib and is administered at a 5 mg dose of PO BID, or at an 11 mg dose of PO QD. In certain embodiments, the JAK inhibitor is desentinib and is administered in a dose of 25 mg, 50 mg, 100 mg, or 150 mg of PO BID. In certain embodiments, the inhibitor is luzotinib and is administered at a dose of 25 mg PO BID, is administered at a dose of 20 mg PO BID, is administered at a dose of 15 mg PO BID, and is administered at a dose of 10 mg PO BID Dosing with or at 5 mg PO BID. 5.11 Other Therapeutics In various embodiments of the methods described herein, the method further comprises administering a therapeutic agent other than an IL-6 antagonist, wherein the second therapeutic agent is also capable of reducing the performance of hypaxidine. In some embodiments, the second therapeutic agent is a BMP antagonist. In certain embodiments, the BMP antagonist is an anti-BMP6 antibody. In specific embodiments, the anti-BMP6 antibody has six CDRs of the antibody described in US 2016/0176956 or US 2016/0159896, the disclosures of which are incorporated herein by reference in their entirety. In certain embodiments, the second therapeutic agent is a hepcidin-modulin antagonist. In a specific embodiment, the hepcidin-modulin antagonist is an anti-hepcidin-modulin antibody. In a specific embodiment, the anti-hepcidin regulatory protein antibody has Kovac et al.,Haematologica (2016) six CDRs of the antibody disclosed in doi: 10.3324 / haematol.2015.140772 [electronic version before printing]. In certain embodiments, the second therapeutic agent is a hypaxidine antagonist. In a particular embodiment, the hypaxidine antagonist is an anti-hypaxidine antibody. In a specific embodiment, the antibody has six CDRs of the antibody described in US 2016/0017032, the disclosure of which is incorporated herein by reference in its entirety. 5.12 Sets In another aspect, sets are provided. In a typical embodiment, the kit provides reagents to determine the patient's identity from a biological sample obtained from the patient.TMPRSS6 Genotype at SNP rs855791. 5.13 Other Aspects and Examples 5.13.1 Methods for Treating Inflammation in Chronic Kidney Disease or Cardiovascular Disease In other aspects and examples, there are provided methods for characterizing and treating chronic kidney disease or cardiovascular disease with IL-6 antagonist Compositions and methods of inflammation, and methods for characterizing a patient's response to treatment. These aspects and examples are based, at least in part, on the finding that having a moiety containing G or C at nucleotide position 2321TMPRSS6 One or more of the dual genes (encoding amino acids containing alanine at position 736)TMPRSS6 Inflammation in patients with chronic kidney disease and cardiovascular disease makes these patients a higher risk of death, and such individuals can be treated with IL-6 antagonists to reduce this risk. As reported in more detail below, patients with chronic kidney disease were genotyped, serum levels of IL-6 and CRP were analyzed, and these diagnostic data were compared with the EPO administration and risk of death. Having a G or C at nucleotide position 2321TMPRSS6 One or more dual genes (encodes the amino acidTMPRSS6 Peptides), and patients with elevated IL-6 and / or CRP levels require higher EPO doses to treat and have higher mortality rates. Nucleotides at this position have been shown to be important in identifying patients with iron deficiency anemia (see Finberg et al.,Nat. Genet. 2008; 40 (5): 569-571, the teachings of which are hereby incorporated by reference in their entirety with respect to sequences, variants, nomenclature, etc.). This information strongly supportsTMPRSS6 Genotyping a subset of patients who require higher EPO doses and / or have a higher risk of death, and will likely have an effect on IL-6 in the presence or absence of standard therapies for the treatment of anemia, such as those associated with chronic kidney disease Suppresses reaction. By inhibiting inflammation, EPO administration can be reduced, thereby avoiding the adverse side effects of EPO (such as cardiovascular risk). These aspects and examples are further based on the finding that having a compound containing G or C at nucleotide position 2321TMPRSS6 One or more dual genes (encodes the amino acidTMPRSS6 Patients) are at a higher risk of death associated with myocardial infarction or cardiovascular disease. These patients will also likely benefit from IL-6 inhibition, which will reduce inflammation and increase the risk. Therefore, the following treatment methods are provided: by inhibiting, for example, by SNP rs855791TMPRSS6 IL-6 biological activity in patients selected for genotyping, by blocking IL-6 or its receptor (gp80) from binding to each other, or blocking their signalling or performance (for example by anti-IL-6 Anti-IL-6R antibody or JAK1 / STAT3 inhibition) to treat inflammation associated with cardiovascular disease or chronic kidney disease (including chronic kidney disease anemia) and / or reduce the risk of death associated with such conditions. In one embodiment, the treatment of chronic kidney disease is performed in the presence or absence of standard treatments for anemia and the following methods: for example, by treating SNP rs855791TMPRSS6 Genotyping and detecting levels of inflammatory markers (eg, increased serum levels of IL-6 and / or CRP) to characterize the response of patients with chronic kidney disease to treatment for anemia. Methods are provided for treating cardiovascular disease or chronic kidney disease anemia and / or reducing deaths associated with chronic inflammation in such patients by administering agents that inhibit the biological activity or performance of IL-6. In some aspects and embodiments, compositions and methods are provided for treating chronic inflammation that promotes death in individuals with chronic kidney disease or cardiovascular disease, and for characterizing a patient's response to such therapies. In specific embodiments, there are provided for characterizing and treating chronic inflammatory anemia and death (e.g., in chronic kidney disease) and for characterizing a patient's response to treatment for anemia (e.g., administration of erythropoietin or erythrocyte stimulating agent) Methods. In one aspect, a method is provided for treating chronic inflammation in a selected individual, the method comprising administering to the individual an IL-6 antagonist, wherein for the treatment, the individual is treated by having an amino acid encoding an amino acid that comprises alanine at position 736TMPRSS6 One or more dual genes of the polypeptide are selected. In another aspect, a method is provided for treating inflammation or chronic inflammation in a selected individual with cardiovascular or chronic kidney disease, the method comprising administering to the individual an IL-6 antagonist (e.g., an anti-IL-6 antibody), Wherein for treatment, an individual by having an amino acid encoding alanine at position 736TMPRSS6 One or more dual genes of the polypeptide are selected. In one embodiment, the method reduces an individual's risk of death. In one embodiment, the individual has a history of myocardial infarction or heart failure. In another aspect, a method is provided for reducing the risk of inflammation and death in a selected individual with cardiovascular or renal disease, the method comprising administering to the individual an IL-6 antagonist (e.g., an anti-IL-6 antibody), wherein the individual has Selected to have an amino acid encoding alanine at position 736TMPRSS6 One or more dual genes of the polypeptide and have increased inflammation relative to the reference. In one embodiment, the individual has a history of myocardial infarction or heart failure. In another aspect, a method is provided for reducing the risk of death in an individual with chronic kidney disease or heart failure, the method comprising administering to the individual an IL-6 antagonist, wherein the individual is identified as having an encoded amino acid position 736 containing alanineTMPRSS6 One or more dual genes of the polypeptide and have increased inflammation relative to the reference. In another aspect, a method of treating anemia in an individual is provided, the method comprising administering to the individual an IL-6 antagonist alone or in combination with a therapy for anemia, wherein the individual is identified as having an amino acid position 736 encoded AlanineTMPRSS6 Polypeptide (also known as stromal protease-2; MT2)TMPRSS6 The nucleic acid molecule has G or C) at nucleotide position 2321 and has increased inflammation relative to the reference. In another aspect, a method of treating anemia in an individual with increased inflammation is provided by administering an IL-6 antagonist alone or in combination with a erythropoietin in an amount effective to neutralize the inflammation of the individual ( (E.g., an IL-6 antibody), the individual has a gene encoding alanine at position 736 of the amino acid.TMPRSS6 One or more dual genes of a polypeptide (e.g., inTMPRSS6 The nucleic acid molecule has G or C at nucleotide position 2321). In yet another aspect, a method is provided for enhancing a response to EPO in an individual identified as in need, the method comprising administering an IL-6 antagonist (e.g., an IL-6 antibody) in an amount effective to neutralize the individual's inflammation. , Thereby reducing the EPO dose, the individual has a protein that encodes alanine at position 736 in the amino acidTMPRSS6 One or more dual genes of a polypeptide (e.g., inTMPRSS6 The nucleic acid molecule has G or C at nucleotide position 2321). In another aspect, a method is provided for reducing the death of an individual with increased inflammation by administering an IL-6 antagonist in an amount effective to neutralize the inflammation of the individual, the individual having an amino acid position encoded 736 containing alanineTMPRSS6 One or more dual genes of a polypeptide (e.g., inTMPRSS6 The nucleic acid molecule has G or C at nucleotide position 2321). In yet another aspect, a method is provided for selecting a therapy for an individual identified as in need, the method comprising: characterizing an individual having a gene encoding an amino acid comprising alanine at position 736 of the amino acidTMPRSS6 One or more dual genes of a polypeptide (e.g., inTMPRSS6 A nucleic acid molecule having G or C at nucleotide position 2321); and detecting the content of one or more inflammation markers, IL-6 or CRP, wherein the characterization indicates that the IL-6 antagonist should be used alone or in combination with a therapy for anemia Vote for. In yet another aspect, methods, methods are provided for increasing the proliferation or survival of red blood cells or progenitor cells (e.g., hematopoietic stem cells, pre-erythroblasts, red blood cells, or reticulocytes) in individuals identified as in need. Comprising administering to a subject an IL-6 antagonist and a erythropoietin, wherein the subject is identified as having a gene encoding alanine at position 736 of the amino acidTMPRSS6 One or more dual genes of a polypeptide (e.g., inTMPRSS6 The nucleic acid molecule has G or C) at nucleotide position 2321 and has increased inflammation relative to the reference. In various embodiments of any of the aspects described herein, the individual has or is identified as having anemia, including cancer anemia, anemia in chronic autoimmune disease, anemia in chronic inflammatory disease, cardiovascular Anemia in diseases, anemia in metabolic syndrome, and similar anemia. In various embodiments of any of the aspects described herein, the individual has or is identified as having chronic kidney disease. In various embodiments of any of the aspects described herein, the individual has or is identified as having inflammation. In various embodiments of any of the aspects described herein, the individual has or is identified as having an increased risk of death associated with chronic inflammation, chronic kidney disease, or cardiovascular disease. In various embodiments of any of the aspects described herein, the individual is identified as in need of treatment. In various embodiments of any of the aspects described herein, the individual has or is identified as having increased inflammation. In various embodiments of any of the aspects described herein, the individual has or is identified as having a protein encoding alanine at position 736 of the amino acidTMPRSS6 One or more dual genes of a polypeptide (e.g., inTMPRSS6 The nucleic acid molecule has G or C) at nucleotide position 2321 and has increased inflammation relative to the reference. In various embodiments of any of the aspects described herein, the method comprises administering an IL-6 antagonist to the individual. In various embodiments of any of the aspects described herein, the method comprises administering an IL-6 antagonist to the individual and a therapy for anemia. In various embodiments of any of the aspects described herein, the individual is a human. In various embodiments of any of the aspects described herein, the treatment for anemia comprises administering a erythropoietin. In various embodiments, the erythropoietin is one or more of erythropoietin, a erythrocyte stimulating agent, a HIF stabilizer, and iron supplementation. In various embodiments, the increased inflammation is characterized by increased IL-6 and / or CRP content relative to the reference group (e.g., as measured by conventional CRP analysis or high sensitivity analysis (hsCRP), both (CRP detection, but different in analysis performance). In various embodiments, the increased inflammation is characterized by an IL-6 greater than about 5 pg / ml. In various embodiments, the increased inflammation is characterized by a CRP greater than about 2 mg / L. In various embodiments of any of the aspects described herein, the IL-6 antagonist is administered in an amount effective to neutralize inflammation. In various embodiments, the amount effective to neutralize inflammation reduces IL-6 to less than about 15 pg / ml, less than about 10 pg / ml, or less than about 5 pg / ml. In various embodiments, the amount effective to neutralize inflammation reduces CRP to less than about 2 mg / L or less than about 0.2 mg / L. In various embodiments of any of the aspects described herein, administration of an IL-6 antagonist or anti-IL-6 antibody reduces the dose of EPO. In certain embodiments, the dose of EPO is reduced by about 40 IU / kg / week, about 50 IU / kg / week, about 80 IU / kg / week, about 100 IU / kg / week or greater than 100 IU / kg / week . In various embodiments, administration of an IL-6 antagonist or anti-IL-6 antibody reduces the side effects of increased EPO dose. In one embodiment, patients with chronic kidney disease are treated in the presence or absence of standard treatments for anemia. More specifically, individuals with chronic kidney disease-related anemia are provided with inhibitory IL-6 in the presence or absence of treatments for anemia (e.g., administration of EPO, ESA, HIF stabilizers, iron supplementation, or red blood cell infusion). Biological activity or manifestation. The treatment for anemia works by stimulating red blood cell production or red blood cell production. Therefore, an agent that increases the growth or proliferation of red blood cells or their progenitor cells and / or reduces the cell death of red blood cells or their progenitor cells can also be administered. Red blood cell progenitor cells include, for example, hematopoietic stem cells, common bone marrow progenitor cells, pre-erythroblasts, red blood cells, reticulocytes, or any cell capable of differentiating or mature into red blood cells. An agent that inhibits the biological activity of IL-6 by blocking IL-6 or its receptor (gp80) from binding to each other or blocking their signalling or expression can be provided as a pharmaceutical composition to individuals with anemia associated with chronic kidney disease Wherein the pharmaceutical composition comprises an effective amount of a medicament, a medicament for treating anemia (for example, EPO, ESA, HIF proline amidino-hydroxylase inhibitor, iron supplementation) and suitable excipients. In one embodiment, the agent is an IL-6 antagonist or anti-IL- that reduces the content or activity of an IL-6 polypeptide or nucleic acid molecule in an individual, or inhibits intracellular signaling triggered by IL-6 receptor activation. 6 antibodies. Anti-IL-6 antibodies (eg, MEDI5117) can be administered in combination with treatments for anemia (eg, administration of EPO, ESA, HIF stabilizers, iron supplementation). The treatment used for anemia depends on the patientTMPRSS6 Genotype and patient's inflammatory status. In the case of treatment for anemia (e.g. administration of EPO, ESA, HIF stabilizers, iron supplementation), for those containing G or C at nucleotide position 2321TMPRSS6 The main dual gene (encodes the amino acid containing alanine at position 736)TMPRSS6 Polypeptides) are homozygous or heterozygous and patients with increased levels of inflammation markers (e.g., IL-6 and / or CRP) are administered with IL-6 antagonists or anti-IL-6 antibodies, which reduces IL-6 The amount or activity of the polypeptide. For those containing A or T at nucleotide position 2321TMPRSS6 Secondary dual gene (encodes the amino acid containing valine at position 736)TMPRSS6 Polypeptides) are homozygous patients who do not require anti-IL-6 therapy to supplement treatment for anemia. The method used for the treatment of anemia may vary depending on the stage of chronic kidney disease, the age of the patient, health status and physical conditions. In another aspect, analysis is provided that is suitable for characterizing individuals with anemia associated with chronic inflammation, such as in chronic kidney disease. The inflammation markers IL-6 and CRP can be detected by any suitable method. The methods described herein can be used individually or in combination for detecting IL-6 or CRP biomarkers and / or inflammatory conditions. In one embodiment, inflammation relative to a reference (e.g., serum from a healthy control individual) is characterized by detecting the amount of IL-6 and / or CRP polypeptide in a biological sample (e.g., serum) of the individual, where Increased IL-6 and / or CRP performance is indicative of inflammation. In another embodiment, an increase in the expression of IL-6 and / or CRP indicates that individuals with anemia associated with chronic kidney disease will not respond to treatment for anemia, and / or when treated with an IL-6 antagonist (e.g., (Anti-IL-6 antibody) in combination will respond to treatment for anemia. In one embodiment, the IL-6 and / or CRP polypeptide content is measured by immunoassay. Immunoassays typically use antibodies (or other agents that specifically bind a marker) to detect the presence or content of a biomarker in a sample. Antibodies can be prepared by methods well known in the art (e.g., by immunizing animals with biomarkers or fragments thereof). Biomarkers can be separated from a sample based on their binding characteristics. Alternatively, if the amino acid sequence of a polypeptide biomarker is known, the polypeptide can be synthesized and used to generate antibodies by methods well known in the art. In various embodiments, traditional immunoassays are used, including, for example, Western blots; sandwich immunoassays, including ELISA and other enzyme immunoassays; fluorescence-based immunoassays, and chemiluminescence. Turbidimetry is an analysis performed in the liquid phase where the antibody is in solution. Binding of an antigen to an antibody causes a change in absorbance, and the absorbance is measured. Other forms of immunoassay include magnetic immunoassay, radioimmunoassay and iqPCR. Other detection methods include liquid chromatography and mass spectrometry. Immunoassays can be performed on solid substrates (e.g. wafers, beads, microfluidic platforms, membranes) or on any other format that supports antibody binding to the label and subsequent detection. A single marker can be detected at once or multiple formats can be used. Multiplex immunoassays may involve planar microarrays (protein wafers) and bead-based microarrays (suspension arrays). Choosing patients with chronic kidney disease identified as anemia with increased levels of IL-6 and / or CRP polypeptides for treatment with an agent that reduces the performance or activity of IL-6 (e.g., anti-IL-6 antibodies) in combination with anemia treatment . Patients treated with the method of the present invention can be monitored by detecting changes in hemoglobin, hematocrit, erythropoietin dose, IL-6 and / or CRP performance after treatment. Patients showing reduced expression of IL-6 and / or CRP and / or reduced inflammation were identified as responding to IL-6 inhibition. Other aspects and examples are provided in the following numbered items. CLAIMS 1. A method of treating chronic inflammation in a selected individual, the method comprising administering an IL-6 antagonist to the individual, wherein the individual selected for treatment has one or more codes encoding alanine at position 736 in the amino acidTMPRSS6 Peptide dual genes. 2. A method of treating inflammation in a selected individual with cardiovascular disease, heart failure, and / or chronic kidney disease, the method comprising administering an IL-6 antagonist to the individual, wherein the individual selected for treatment has one or more codes comprising Alanine at position 736 of amino acidTMP RSS6 Peptide dual genes. 3. A method of reducing the risk of inflammation and death in a selected individual with cardiovascular disease, heart failure and / or chronic kidney disease, the method comprising administering an IL-6 antagonist to the individual, wherein the individual is selected to have one or more Codes containing alanine at amino acid position 736TMPRSS6 A dual gene of a polypeptide and has increased inflammation relative to a reference. 4. A method of treating anemia in an individual with chronic kidney disease, the method comprising administering an IL-6 antagonist to the individual, wherein the individual is identified as having an amino acid that encodes alanine at position 736 in the amino acidTMPRSS6 One or more dual genes of the polypeptide and have increased inflammation relative to the reference. 5. The method according to any one of clauses 1 to 4, wherein the IL-6 antagonist is administered in an amount effective to neutralize inflammation. 6. The method according to any one of clauses 1 to 4, wherein the IL-6 antagonist is an anti-IL-6 antibody. 7. The method of clause 5, wherein the method further comprises administering a erythropoietin to the individual. 8. The method of any one of clauses 1 to 4, wherein the method reduces the risk of death of the individual. 9. A method of reducing the risk of death in an individual with chronic kidney disease or heart failure, the method comprising administering to the individual an IL-6 antagonist, wherein the individual is identified as having a gene encoding alanine at position 736TMPRSS6 One or more dual genes of the polypeptide and have increased inflammation relative to the reference. 10. A method of treating anemia in an individual with increased inflammation, the method comprising: administering an erythropoietin and an anti-IL-6 antibody in an amount effective to neutralize the individual's inflammation, the individual having an AlanineTMPRSS6 One or more dual genes of a polypeptide. 11. The method of any one of clauses 1 to 10, wherein the increased inflammation is characterized by an increased IL-6 and / or CRP content relative to a reference. 12. The method of clause 11, wherein the increased inflammation is characterized by an IL-6 greater than about 5 pg / ml, about 10 pg / ml, or about 15 pg / ml. 13. The method of clause 10, wherein the increased inflammation is characterized by a CRP greater than about 2 mg / L. 14. The method of clause 10, wherein the erythropoietin is one or more of erythropoietin, a erythrocyte stimulating agent, a HIF stabilizer, and iron supplementation. 15. A method for enhancing a response to EPO in an individual identified as in need, the method comprising administering an IL-6 antagonist or an anti-IL-6 antibody in an amount effective to neutralize the inflammation of the individual, thereby enhancing the Response to EPO, the individual has a gene encoding alanine containing amino acid position 736TMPRSS6 One or more dual genes of a polypeptide. 16. The method of clause 15, wherein the amount of the anti-IL-6 antibody effective to neutralize inflammation reduces IL-6 to less than about 15 pg / ml, less than about 10 pg / ml, or less than about 5 pg / ml. 17. The method of clause 16, wherein the amount of the IL-6 antagonist or anti-IL-6 antibody effective to neutralize inflammation reduces CRP to less than about 2 mg / L. 18. The method of clause 15, wherein the administration of an IL-6 antagonist or an anti-IL-6 antibody reduces the dose of EPO. 19. The method of clause 17, wherein the dose of EPO is reduced by about 40 IU / kg / week, about 50 IU / kg / week, about 80 IU / kg / week, about 100 IU / kg / week or greater than 100 IU / kg / week. 20. The method of clause 15, wherein the administration of an IL-6 antagonist or an anti-IL-6 antibody reduces the side effects of increased EPO. 21. A method of selecting a therapy for an individual identified as in need, the method comprising: a) characterizing the individual as having an amino acid that encodes alanine at position 736 of the amino acidTMPRSS6 One or more dual genes of the polypeptide; and b) detecting the content of one or more inflammation markers IL-6 and CRP, wherein the characterization indicates that the IL-6 antagonist should be administered in combination with a therapy for anemia. 22. The method of clause 21, wherein the method further comprises administering an IL-6 antagonist and a therapy for anemia to the individual. 23. The method of clause 21, wherein the treatment for anemia comprises administering a erythropoietin. 24. A method for increasing the proliferation or survival of red blood cells or progenitor cells in an individual identified as in need thereof, the method comprising administering to the individual an IL-6 antagonist and a erythropoietin, wherein the individual is identified as having Encodes an amino acid containing alanine at position 736TMPRSS6 One or more dual genes of a polypeptide, and wherein the individual has increased inflammation relative to a reference. 25. The method of clause 24, wherein the method reduces cell death of red blood cells or their progenitor cells. 26. The method of clause 24, wherein the progenitor cells are hematopoietic stem cells, pre-erythroblasts, red blood cells, or reticulocytes. 27. The method of any one of clauses 15 to 24, wherein the individual has chronic kidney disease. 28. The method of any one of clauses 15 to 24, wherein the individual has anemia. 29. The method of clause 28, wherein the anemia is cancer anemia, anemia in chronic autoimmune disease, anemia in chronic inflammatory disease, or anemia in metabolic syndrome. 30. The method of any one of clauses 15 to 24, wherein the IL-6 antagonist is administered in an amount effective to neutralize inflammation. 31. The method of any one of clauses 15 to 24, wherein the IL-6 antagonist is an anti-IL-6 antibody. 32. The method of any one of clauses 15 to 24, wherein the increased inflammation is characterized by an increased IL-6 and / or CRP content relative to a reference. 33. The method of any one of clauses 15 to 24, wherein the increased inflammation is characterized by an IL-6 greater than about 5 pg / ml, about 10 pg / ml, or about 15 pg / ml. 34. The method of any one of clauses 15 to 24, wherein the increased inflammation is characterized by a CRP greater than about 2 mg / L. 35. The method of any one of clauses 15 to 24, wherein the amount effective to neutralize inflammation reduces IL-6 to less than about 10 pg / ml or less than about 5 pg / ml. 36. The method of any one of clauses 15 to 24, wherein the amount effective to neutralize inflammation reduces CRP to less than about 2 mg / L. 37. The method of any one of clauses 15 to 24, wherein the erythropoietin is one or more of erythropoietin, a erythrocyte stimulating agent, a HIF stabilizer, and iron supplementation. 38. The method of clause 24, wherein the administration of an IL-6 antagonist reduces the dose of EPO. 39. The method of item 38, wherein the IL-6 antagonist is an anti-IL-6 antibody. 40. The method of item 38, wherein the dose of EPO is reduced by about 40 IU / kg / week, about 50 IU / kg / week, about 80 IU / kg / week, about 100 IU / kg / week or more than 100 IU / kg / week. 41. The method of clause 23, wherein the administration of an IL-6 antagonist reduces the side effects of increased EPO. 42. The method of any one of clauses 1 to 40, wherein the dual gene is inTMPRSS6 G is contained at position 2321 of the polynucleotide. 43. The method of any one of clauses 1 to 42, wherein the IL-6 antagonist is an anti-IL-6 antibody having one or more CDRs selected from the following nucleic acid sequences: SNYMI (SEQ ID NO: 12); DLYYYAGDTYYADSVKG (SEQ ID NO: 13); WADDHPPWIDL (SEQ ID NO: 14); RASQGISSWLA (SEQ ID NO: 15); KASTLES (SEQ ID NO: 16); and QQSWLGGS (SEQ ID NO: 17). 44. The method of item 42, wherein the anti-IL-6 antibody has a heavy chain CDR1 comprising the sequence SNYMI (SEQ ID NO: 12); a heavy chain CDR2 comprising the sequence DLYYYAGDTYYADSVKG (SEQ ID NO: 13); and a sequence comprising the sequence WADDHPPWIDL ( CDR3 of heavy chain (SEQ ID NO: 14); CDR1 of light chain comprising the sequence RASQGISSWLA (SEQ ID NO: 15); CDR2 of light chain comprising the sequence (SEQ ID NO: 16); and QQSWLGGS (SEQ ID NO 17) of the sequence Light chain CDR3. 45. The method of item 42, wherein the anti-IL-6 antibody has a heavy chain comprising the following sequence: . 46. The method of item 42, wherein the anti-IL-6 antibody has a light chain comprising the following sequence: . 47. The method of item 42, wherein the anti-IL-6 antibody is MEDI5117. 48. The method of any one of clauses 1 to 47, wherein the individual is a human. 5.13.2 Methods for treating cardio-renal syndrome In other aspects and embodiments, compositions and methods for treating cardio-renal syndrome are provided. These aspects and examples are based at least in part on the finding that anti-IL-6 treatment of heart injury in a rodent model of cardio-renal syndrome has an equivalent effect to standard care treatment. As reported in more detail below, after myocardial infarction, rodent models of cardio-renal syndrome are treated with anti-IL-6 or standard care therapies (ACE inhibitors, perindopril). After treatment, the ejection fraction, cardiac contractility and the percentage of fibrotic tissue in cardiac tissue were measured. The degree of ejection fraction was increased in the group of individuals treated with anti-IL-6 and in the group of individuals treated with standard care therapy compared to the content in the group of individuals treated with the control therapeutic agent. The myocardial contractility was increased in both the anti-IL-6 treated group and the standard care therapy group compared to the content in the individual group treated with the control therapeutic agent. The amount of fibrotic tissue in both the group treated with anti-IL-6 and the group treated with standard care therapy was reduced compared to the amount in the individual group treated with the control therapeutic agent. In addition, the degree of ejection fraction and the amount of fibrotic tissue were similar in the group of individuals treated with anti-IL-6 and the group of individuals treated with standard care therapy. The results indicate that anti-IL-6 therapy is equivalent to standard care therapy in treating cardio-renal syndrome in rodent models. These aspects and examples are further based, at least in part, on the finding that patients identified as having a cardio-renal syndrome after myocardial infarction and having elevated IL-6 levels are particularly at increased risk of cardiovascular death, including heart failure. Without being bound by theory, IL-6 may play a causative role in the development and / or progression of cardio-renal syndrome. Therefore, patients with elevated IL-6 content after myocardial infarction or patients with cardiorenal syndrome and elevated IL-6 content may benefit from IL-6 inhibition. Therefore, a method of treating heart and / or kidney damage in an individual with a cardiorenal syndrome is provided, which involves administering an IL-6 antagonist to the individual. In some embodiments, heart and / or kidney damage in individuals with cardio-renal syndrome is treated in the presence or absence of standard treatments for cardio-renal syndrome. A method for characterizing the risk of cardiovascular death in a patient after myocardial infarction is also provided, which method involves detecting an increase in the amount of IL-6 in a biological sample obtained from the patient. In one aspect, a method of treating heart and / or kidney damage in an individual with a cardiorenal syndrome is provided, which method involves administering an IL-6 antagonist to the individual. In another aspect, a method of increasing cardiac function in an individual with a cardiorenal syndrome is provided, which method involves administering an IL-6 antagonist to the individual. In yet another aspect, a method of reducing fibrosis in an individual with a cardiorenal syndrome is provided, which method involves administering an IL-6 antagonist to the individual. In various embodiments of any of the aspects described herein, the method further involves administering standard care therapies to the individual. In various embodiments, the standard care therapy is an angiotensin-converting enzyme (ACE) inhibitor. In various embodiments of any of the aspects described herein, the increase in cardiac function is characterized by an increase in the ejection fraction and / or myocardial contractility of the individual relative to the reference group. In various embodiments of any of the aspects described herein, the reduction in fibrosis is characterized by a reduction in the percentage of fibrotic tissue in a tissue sample from an individual relative to a reference group. In various embodiments, the fibrosis is in cardiac tissue. In various embodiments of any of the aspects described herein, the individual has a heart and / or kidney injury. In various embodiments of any of the aspects described herein, the individual has a heart injury and subsequently a kidney injury. In another aspect, the present invention provides a method for identifying an increased risk of cardiovascular death (e.g., heart failure) in an individual after myocardial infarction in the individual, which method involves measuring IL- in a sample from the individual relative to a reference group. A content of one or more of the 6 polynucleotides or polypeptides, wherein an increase in the content of one or more of the IL-6 polynucleotides or polypeptides indicates an increased risk of cardiovascular death. In yet another aspect, the present invention provides a method for characterizing the risk of cardiovascular death (e.g., heart failure) in an individual after a myocardial infarction in an individual, the method involving measuring IL-6 polynuclei in a sample from a reference relative to the individual The content of one or more of the nucleotides or polypeptides, wherein an increased content of one or more of the IL-6 polynucleotide or polypeptide is indicative of an increased risk of cardiovascular death. In various embodiments of any of the aspects described herein, the individual has a cardio-renal syndrome, heart failure, chronic kidney disease, or cardiorenal disease. In various embodiments of any of the aspects described herein, the individual is identified as having a cardio-renal syndrome, heart failure, chronic kidney disease, or cardiorenal disease approximately one month after myocardial infarction. In another aspect, the invention provides a method of treating heart and / or kidney injury in a selected individual with a cardiorenal syndrome, the method comprising administering an IL-6 antagonist to the individual, wherein the individual is The detection is selected to increase the amount of one or more of the IL-6 polynucleotide or polypeptide relative to the reference biological sample from the individual. In yet another aspect, the present invention provides a method for reducing the risk of cardiovascular death (e.g., heart failure) in a selected individual with cardio-renal syndrome, the method involving administering an IL-6 antagonist to the individual, wherein the Detection is selected relative to a reference to an increase in one or more of the IL-6 polynucleotide or polypeptide in a biological sample from the individual. In various embodiments of any of the aspects described herein, the individual has a myocardial infarction. In various embodiments of any of the aspects described herein, the IL-6 antagonist is an anti-IL-6 antibody. In various embodiments, the anti-IL-6 antibody is MEDI5117. In various embodiments of any of the aspects described herein, the biological sample is a plasma sample or a serum sample. In various embodiments of any of the aspects described herein, the individual is a human. In another aspect, methods are provided for treating a patient's cardiorenal syndrome and / or reducing the risk of death or heart failure in such patients by administering an agent that inhibits the biological activity or performance of IL-6. In one embodiment, patients with cardio-renal syndrome are treated in the presence or absence of standard treatments for cardio-renal syndrome, such as angiotensin-converting enzyme (ACE) inhibitors. Specifically, an agent that inhibits the biological activity or expression of IL-6 is provided to an individual suffering from cardio-renal syndrome (for example, administration of an anti-IL-6 antibody). In another aspect, a method of increasing cardiac function and a method of reducing fibrosis in an individual suffering from cardio-renal syndrome are provided. The method comprises administering to an individual an agent that inhibits the biological activity or performance of IL-6. In some embodiments, increased cardiac function is characterized by an increase in the ejection fraction of an individual relative to a reference (e.g., a healthy control subject's ejection fraction), or a myocardial contraction relative to a reference (e.g., myocardial contractility of a healthy control subject) (E.g. dP / dtmaximum ). In some embodiments, the reduction in fibrosis is characterized by a reduction in the percentage of fibrotic tissue in a tissue sample from an individual relative to a reference (eg, a tissue sample obtained from a healthy control individual). In one embodiment, the fibrosis is in cardiac tissue. An agent that inhibits the biological activity of IL-6 by blocking IL-6 or its receptor (gp80) from binding to each other or blocking their signal transmission or expression can be provided as a pharmaceutical composition to individuals suffering from cardio-renal syndrome, wherein the pharmaceutical combination The substance contains an effective amount of a medicament and a suitable excipient. In one embodiment, the agent is an IL-6 antagonist or anti-IL-6 that reduces the content or activity of an IL-6 polypeptide or polynucleotide in an individual, or inhibits intracellular signaling triggered by IL-6 receptor activation. IL-6 antibody. Anti-IL-6 antibodies (eg, MEDI5117) can be administered. The method used for the treatment of cardio-renal syndrome may vary depending on the stage of the cardio-renal syndrome, the age of the patient, the health status and physical conditions. In various embodiments, individuals with cardio-renal syndrome are treated with an IL-6 antagonist. In addition, individuals with an increased risk of cardiovascular death and / or heart failure after myocardial infarction can be identified by characterizing the plasma IL-6 content in the individual. Individuals with elevated IL-6 content have an increased risk of cardiovascular death and / or heart failure. For treatment with an IL-6 antagonist, such individuals may be selected. In addition, individuals suffering from cardio-renal syndrome and having an increased IL-6 content, including such individuals who have suffered a myocardial infarction, may be selected for treatment. After selecting for treatment, such individuals can be administered with almost any IL-6 antagonist known in the art. Suitable IL-6 antagonists include, for example, IL-6 antagonists, commercially available IL-6 antagonists, IL-6 antagonists developed using methods well known in the art, and targeting IL-6R-related Antagonists of the intracellular signaling system. In another aspect, analysis is provided for characterizing the risk of cardiovascular death, heart failure, and / or death in an individual after myocardial infarction. The analysis provides detection of IL-6 in biological samples obtained from the individual. IL-6 can be detected by any suitable method. In one embodiment, the risk of cardiovascular death or heart failure is determined by detecting the performance of the organism relative to a reference (e.g., serum or plasma from a healthy control individual or from a control individual without heart-renal disease). The level of IL-6 polypeptide in a sample (eg, serum or plasma) is characterized, where an increase in IL-6 is indicative of an increased risk of cardiovascular death or heart failure. Individuals identified as having an increased risk of cardiovascular death, heart failure or death can be selected for treatment. In another embodiment, for treatment with an IL-6 antagonist (e.g., an anti-IL-6 antibody), an individual suffering from a cardiorenal syndrome and having an increased IL-6 content is selected. In one embodiment, the IL-6 polynucleotide content is measured. The content of IL-6 polynucleotides can be measured by standard methods such as quantitative PCR, Northern blot, microarray, mass spectrometry, and in situ hybridization. In one embodiment, the IL-6 polypeptide content is measured. The amount of IL-6 polypeptide can be measured by standard methods, such as by immunoassay. Immunoassays typically use antibodies (or other agents that specifically bind a marker) to detect the presence or content of a biomarker in a sample. Antibodies can be prepared by methods well known in the art (e.g., by immunizing animals with biomarkers or fragments thereof). Biomarkers can be separated from a sample based on their binding characteristics. Alternatively, if the amino acid sequence of a polypeptide biomarker is known, the polypeptide can be synthesized and used to generate antibodies by methods well known in the art. In various embodiments, the analysis uses traditional immunoassays, including, for example, Western blots; sandwich immunoassays, including ELISA and other enzyme immunoassays; fluorescence-based immunoassays and chemiluminescence. Turbidimetry is an analysis performed in the liquid phase where the antibody is in solution. The combination of antigen and antibody results in a change in absorbance, which is measured. Other forms of immunoassay include magnetic immunoassay, radioimmunoassay and iqPCR. Other detection methods include liquid chromatography and mass spectrometry. Immunoassays can be performed on solid substrates (eg, wafers, beads, microfluidic platforms, membranes) or in any other format that supports the binding of antibodies to labels and subsequent detection. Single markers can be detected at once or multiple formats can be used. Multiplex immunoassays can involve planar microarrays (protein wafers) and bead-based microarrays (suspension arrays). For treatment with agents that reduce the performance or activity of IL-6 (eg, anti-IL-6 antibodies), patients with cardiorenal syndrome identified as having increased IL-6 polypeptide content are selected. Therapeutic agents can be administered in combination with standard treatments (such as ACE inhibitors) for cardio-renal syndrome. Patients treated with the method of the present invention can be monitored by detecting changes in IL-6 after treatment. Other aspects and examples are provided in the following numbered items. What is claimed is: 1. A method of treating heart and / or kidney injury in an individual with a cardiorenal syndrome, the method comprising administering an IL-6 antagonist to the individual. 2. A method of increasing cardiac function in an individual with a cardiorenal syndrome, the method comprising administering an IL-6 antagonist to the individual. 3. A method of reducing fibrosis in an individual suffering from cardio-renal syndrome, the method comprising administering an IL-6 antagonist to the individual. 4. The method of item 2, wherein the increase in cardiac function is characterized by an increase in the ejection fraction of the individual relative to the reference group. 5. The method of clause 3, wherein the fibrosis is in cardiac tissue. 6. The method according to item 3 or 5, wherein the reduction in fibrosis is characterized by a decrease in the percentage of fibrotic tissue in the tissue sample from the individual relative to the reference group. 7. The method of any one of clauses 1 to 6, wherein the individual has a heart and / or kidney injury. 8. The method of any one of clauses 1 to 7, wherein the individual has a heart injury and subsequently a kidney injury. 9. The method of any one of clauses 1 to 8, further comprising administering standard care therapies to the individual. 10. The method of any one of clauses 1 to 9, wherein the standard care therapy is an angiotensin-converting enzyme (ACE) inhibitor. 11. A method for identifying an increased risk of cardiovascular death in an individual after a myocardial infarction, the method comprising measuring an amount of one or more of IL-6 polynucleotides or polypeptides relative to a reference sample from the individual Content, where an increased content of one or more of the IL-6 polynucleotide or polypeptide is indicative of an increased risk of cardiovascular death. 12. A method of characterizing the risk of cardiovascular death in an individual after myocardial infarction, the method comprising measuring the content of one or more of IL-6 polynucleotides or polypeptides relative to a reference sample from the individual, An increase in one or more of the IL-6 polynucleotides or polypeptides indicates an increased risk of cardiovascular death. 13. The method of clause 11 or 12, wherein the individual has cardio-renal syndrome, heart failure, chronic kidney disease, or no cardio-renal disease. 14. The method of any one of clauses 11 to 13, wherein the individual is identified as having a cardio-renal syndrome, heart failure, chronic kidney disease, or acardio-renal disease approximately one month after myocardial infarction. 15. A method of treating heart and / or kidney injury in a selected individual with a cardiorenal syndrome, the method comprising administering an IL-6 antagonist to the individual, wherein for the treatment, the individual is detected by detection relative to the reference from the individual The increased amount of one or more of the IL-6 polynucleotide or polypeptide in the biological sample is selected. 16. A method for reducing the risk of cardiovascular death in a selected individual with a cardio-renal syndrome, the method comprising administering to the individual an IL-6 antagonist, wherein the individual increases the amount of The content of one or more of the IL-6 polynucleotide or polypeptide is selected. 17. The method of clause 15 or 16, wherein the individual has suffered a myocardial infarction. 18. The method according to any one of clauses 1 to 10 or 15 to 17, wherein the IL-6 antagonist is an anti-IL-6 antibody. 19. The method of clause 18, wherein the anti-IL-6 antibody is MEDI5117. 20. The method according to any one of clauses 11 to 19, wherein the biological sample is a plasma sample. 21. The method of any one of clauses 1 to 20, wherein the individual is a human. 5.14 Examples The following examples are provided by way of illustration and not limitation. 5.14.1 Example 1: EPO dose and overall survival in patients with chronic kidney diseaseTMPRSS6 SNP rs855791 The serum IL-6 and CRP content-related peptide hormone hypaxidine plays a major role in systemic iron homeostasis in patients with at least one replica of the primary dual gene. Hentze et al.,Cell 142: 24-38 (2010). Hypaxidine is known to be affected byTMPRSS6 The gene product is affected by interstitial protease-2, which is a type II transmembrane serine protease. DisplayedTMPRSS6 Common variants of genes are associated with iron status, Benyamin et al.,Nature Genetics 41 (11): 1173-1175 (2009) and shownTMPRSS6 Certain mutations in the gene cause iron-refractory iron deficiency anemia (IRIDA), Finberg et al.,Nature Genetics 40 (5): 569-571 (2008). SNP rs855791 (2321G → A; A736V) isTMPRSS6 Naturally occurring variants of genes are associated with naturally occurring variants in terms of hypaxidine performance and blood hemoglobin content. For judgmentTMPRSS6 Whether the genotype at rs855791 SNP predicts the degree of anemia in end-stage renal disease, combined with the newly determined SNP genotyping, analyze data collected in clinical studies of patients with chronic kidney disease previously. Since the performance of Hypaxidine is also regulated by IL-6, Casanovas et al.,PLOS Computational Biol. 10 (1): e1003421 (2014). Data were also analyzed to determine whether serum IL-6 levels could predict the degree of anemia in end-stage renal disease.method Based on universal dialysis criteria, ferritin> 100 ng / mL and Hb> 10 mg / dL, selected from MIMICK1, MIMICK2 (location of inflammation markers in chronic kidney disease) and MIA (malnutrition, inflammation and atherosclerosis) The data of N = 257 patients in the sclerosis) group were managed to N = 208 to select patients with stable hemodialysis in the absence of iron deficiency anemia and in the absence of labeled anemia, and thus did not include patients with autologous red blood. Patients with factors that separate iron transport factors were recruited in six dialysis units in the Stockholm-Uppsala (Sweden) district during the time period October 2003-September 2004. All patients' clinical data, including erythropoietin (EPO) dose in IU / kg / week, IL-6 serum content in pg / ml, CRP serum content in mg / L, and month Survival of the unit and SNP rs855791TMPRSS6 Genotypes were proofread and analyzed using statistical analysis software (SPSS Statistical Desktop; IBM). ResearchedTMPRSS6 The dual genes and their nucleotides and amino acids are indicated in Table 1. Divide the group into rs855791 subgroups (homotype AA, heterotype AG, and homotype GG), and divide each genotype component into serum IL-6 content (for example, IL-6 <5pg / compared to> 10 pg / ml ml, and compared with> 15 pg / ml, IL-6 <5 pg / ml) or serum CRP content (compared with> 2 mg / L, CRP <2 mg / L) in the third or fourth quartile. EPO doses were compared in the top and bottom tertiles and quartiles. Statistician analyses were performed within the genotype group by Students T-Test and between the groups by ANOVA.result Since the EPO dose of each patient has been titrated by the treating physician to obtain normal heme content, the EPO dose can be used as a proxy for the level of anaemia. It was found that EPO doses in individuals who were homozygous (A / A) for the minor dual gene were relatively insensitive to the variant of IL-6 (Figure 1A; left panel). However, the EPO dose in individuals with at least one replica of the major dual gene-for patients whose major dual gene (G) is heterozygous (A / G) or homozygous (G / G)-is sensitive to the IL-6 content of the individual (Figure 1B; right). In these latter individuals, increased serum IL-6 content (e.g.,> 5 pg / ml) was associated with increased EPO dose. Without being bound by a particular theory, the effect of homozygous removal of IL-6 under minor dual genes on iron transport. Therefore, regardless of IL-6 content, the EPO dose in these patients (A / A) was approximately the same. Not related to IL-6 contentTMPRSS6 rs855791 Individuals whose minor dual genes (A) were homozygous exhibited similar deaths (Figure 2A). However, the survival rate of individuals with at least one replica of the primary dual gene-for patients whose primary dual gene (G) is heterozygous or homozygous-varies according to IL-6 content (Figure 2B). In fact, in response to elevated IL-6 levels in individuals with chronic kidney disease with stage 5 dialysis,TMPRSS6 The G-dual gene confers higher deaths for various reasons. In individuals with at least one replica of the primary dual gene (G), the IL-6 content (i.e., medium) And IL-6) were associated with increased mortality (Figure 2B). The content of the acute phase reactant CRP-inflammation marker- was also related to the increased EPO dose in individuals with heterozygous or homozygous genes for the major dual gene (G), but in patients with homozygous secondary genes Not so in China (Figure 3).Discourse As shown in Figure 1,TMPRSS6 In patients with at least one replica of the primary dual gene at rs855791 SNP, the degree of basal anemia-measured as the clinically titrated EPO dose-is related only to IL-6 content. In these patients, the higher the serum IL-6 content, the higher the required EPO dose (Figure 1B). In contrast, the degree of anemia in patients with two copies of the secondary dual gene was not related to serum IL-6 content (Figure 1A). Similarly, in havingTMPRSS6 In patients with at least one replica of the major dual gene at SNP rs855791, overall survival was only related to IL-6 content. In havingTMPRSS6 In individuals with at least one copy of the rs855791 primary dual gene, survival rates are inversely related to serum IL-6 levels, with patients at the highest levels of serum IL-6 levels compared to patients at the lowest levels of IL-6 levels With statistically significantly worse survival rates (Figure 2B). In contrast, the overall survival rate of patients with homozygous secondary genes at rs855791 was not affected by IL-6 content (Figure 2A). Without intending to be bound by theory, in havingTMPRSS6 In patients with at least one replica of the primary dual gene, an increase in serum IL-6 can promote an increase in hypaxidine performance, thereby increasing anemia. The increased risk of death is the result of dysfunctional iron metabolism, the resulting anemia, and / or increased doses of erythrocyte stimulating agents such as EPO. If these correlations reflect a causal relationship, it raises the possibility that, in patients with chronic kidney disease, reduced IL-6 content or IL-6 signaling may reduce anemia, reduce the required EPO dose, and increase Survival rate, but only ifTMPRSS6 rs855791 has the largest effect in their patients with at least one replica of the dual gene, and in their patients with elevated serum IL-6 content. 5.14.2 Example 2: Risk of death and risk of heart failure after acute myocardial infarctionTMPRSS6 SNP rs855791 Serum levels of IL-6 in patients with at least one replica of a major dual gene were determined to be in patients with acute rather than chronic diseaseTMPRSS6 Whether the rs855791 genotype affects IL-6 sensitivity, combined with newly identified SNP genotypes, analyzes data collected in clinical studies of patients previously hospitalized for acute coronary syndromes.method Individual analysis from previously selected multicenter studies of platelet suppression and patient outcomes (PLATO). Patients who are hospitalized with an acute coronary syndrome (with symptom onset during the previous 24 hours) are eligible for admission to PLATO. Mortality and the presence of heart failure were measured in these individuals starting 30 days after myocardial infarction.result AgainstTMPRSS6 The death of rs855791 SNP minor dual gene (A) in individuals who are homozygous was not associated with variants of IL-6 (Figure 4A). However, in response to elevated IL-6 content in individuals after myocardial infarction, one or two copies of the primary dual gene (G) confer higher deaths of various causes (Figure 4B). therefore,TMPRSS6 Regulates IL-6-mediated death risk after myocardial infarction. Also measured in individuals enrolled in PLATO starting 30 days after myocardial infarctionTMPRSS6 Effects of genotypes on the risk of IL-6-mediated heart failure. Heart failure in individuals who are homozygous for the secondary dual gene (A) is not associated with a variant of IL-6 (Figure 5A). However, in response to elevated IL-6 levels in individuals after myocardial infarction,TMPRSS6 The G-dual gene confers a higher rate of heart failure (Figure 5B). therefore,TMPRSS6 Regulates the risk of IL-6-mediated heart failure after myocardial infarction.Discourse This information indicatesTMPRSS6 The correlation between genotype, IL-6 content, and adverse clinical outcomes is not limited to patients with chronic kidney disease. Without intending to be bound by theory, in havingTMPRSS6 In patients with at least one replica of the primary dual gene, an increase in serum IL-6 can drive an increase in hypaxidine performance, followed by an increase in iron chelation in cardiac muscle cells, followed by iron-mediated cytotoxicity. If these correlations reflect causality, it raises the possibility that reduced IL-6 content or IL-6 signaling could reduce heart failure and death in patients with acute coronary syndromes, but onlyTMPRSS6 rs855791 has the largest effect in their patients with at least one replica of the dual gene, and in their patients with elevated serum IL-6 content. 5.14.3 Example 3: Confirmation of in vitro studies on human cardiomyocytes derived from iPSTMPRSS6 Causal relationship between genotype and IL-6-mediated cytotoxicity, although the correlations observed in Examples 1 and 2 suggest thatTMPRSS6 rs855791 In patients with at least one replica of a major dual gene, elevated IL-6 levels, and anemia or hepasidine-mediated cytotoxicity, reduced IL-6-mediated signaling should provide clinical benefit, but the observed Relevance does not prove causality. Therefore, experiments were performed in cardiomyocytes (iPS-CMs) derived from human-induced pluripotent cells to query the effects of BMP and BMP plus IL-6 on the performance of hypaxidine and the susceptibility of cells to ischemic injury. For these cardiomyocytesTMPRSS6 The mutant was transfected. 5.14.3.1 MethodOriginated from human iPS Of Cardiomyocyte culture - ICell cardiomyocytes (Cellular Dynamics International, CDI Inc.) were coated on 6- or 96-well cell culture plates with 0.1% gelatin-coated iCell cardiomyocyte inoculation medium (CDI Inc.). Forty-eight hours after inoculation, the inoculation medium was replaced with maintenance medium (CDI Inc.). The maintenance medium was changed every other day to the days when the experiment was performed.Simulated ischemia / Reoxygenation protocol - As previously reported, iPS cardiomyocytes were subjected to simulated ischemia (SI) for 90 minutes by replacing the cell culture medium with "ischemic buffer", which contains 118 mm NaCl, 24 mm NaHCO3 , 1.0 mm NaH2 PO4 , 2.5 mm CaCl2 -2H2 O, 1.2 mm MgCl2 , 20 mm sodium lactate, 16 mm KCl, 10 mm 2-deoxyglucose (pH adjusted to 6.2) (Das, A., Xi, L., and Kukreja, K. C. (2005)J. Biol. Chem 280: 12944-12955; Das A, Smolenski A, Lohmann SM, Kukreja RC. (2006)J. Biol Chem. 281 (50): 38644-52). Adjust 1-2% O during the entire SI time period2 And 5% CO2 Cells were grown in a tri-gas incubator at 37 ° C. Reoxygenation (RO) is achieved by replacing ischemic buffer with normal cell culture medium under normoxic conditions. Cells were necrotic after 2 or 18 hours of reoxygenation, respectively. As above, iCells experience 4 hours SI and 24 hours RO.Evaluation of cell viability and apoptosis -Perform trypan blue exclusion analysis to analyze cell necrosis as previously reported (Das, A., Xi, L., and Kukreja, K. C. (2005)J. Biol. Chem 280, 12944-12955; Das A, Smolenski A, Lohmann SM, Kukreja RC. (2006)J. Biol. Chem 281 (50): 38644-52).iCell Transfection of cardiomyocytes -On day 8 after seeding, replace the medium with fresh maintenance medium and incubate the cells for 4 hours. Use ViaFect according to the manufacturer's instructions (Promega Corp., Madison, WI)TM Transfection reagent, cells were transfected with pCMV6-XL5 TMPRSS6 (K523) or pCMV6-XL5 TMPRSS6 (K523) V763A. 48 hours after transfection, the cells were subjected to other experiments.Western blot analysis -Perform Western blots as previously described (Das, A., Xi, L., and Kukreja, K. C. (2005)J. Biol. Chem 280, 12944-12955; Das A, Smolenski A, Lohmann SM, Kukreja RC. (2006)J. Biol. Chem 281 (50): 38644-52). Total soluble proteins were extracted from cells with lysis buffer (Cell Signaling, MA). The homogenate was centrifuged at 10,000 x g for 5 minutes at 4 ° C, and the supernatant layer was recovered. Proteins (50 μg from each sample) were separated from a 12% acrylamide gel and transferred to a nitrocellulose membrane, and then in TBST (10 mm Tris-HCl, pH 7.4, 100 mm NaCl, and 0.1% Tween 20) Block with 5% skimmed milk powder for 1 hour. For each of the individual proteins, the rabbit single / multiple or goat multiple primary antibodies were then incubated with the membrane overnight at a dilution of 1: 1000. These individual proteins, namely phospho-benzyl chloride ( Beclin) -1 (Ser93) (D9A5G) rabbit monoclonal antibody, benzyl chloride-1, SQSTM1 / p62, LC3A / B (D3U4C) XP® rabbit monoclonal antibody, phosphate-Akt (Ser473) (D9E) XP® family Rabbit mAb, Akt (pan) (C67E7) Rabbit mAb, Phospho-S6 Ribosomal Protein (Ser240 / 244) (D68F8) XP® Rabbit mAb, S6 Ribosomal Protein (5G10) Rabbit mAb (from Cell Signaling, MA), anti-interstitial proteinase 2 (TMPRSS6) and anti-SLC40A1 (ferritin) (from Abcam Company, MA), and goat actin-HRP (Santa Cruz Biotechnology, TX). The membrane was then incubated with a secondary antibody (1: 2000 dilution; Amersham Biosciences) against rabbit horseradish peroxidase binding for 2 hours. Ink dots were developed using a chemiluminescence system, and the bands were scanned and quantified by densitometry analysis.immediate PCR- Tuckerman analysis (Taqman assay) -Isolation of total RNA including small RNAs using miRNeasy micro kits according to the manufacturer's protocol (QIAGEN Sciences, MD, USA). A Nanodrop ND-1000 spectrophotometer (Agilent technologies, CA, USA) was used to measure the concentration and purity of the isolated RNA. Briefly, 1 μg of total RNA was converted into cDNA using random hexamers using a high-capacity cDNA synthesis kit (Applied Biosystems, CA, USA). The reverse transcription reaction was performed using the following PCR conditions: 25 ° C for 10 minutes; 37 ° C for 120 minutes and 85 ° C for 5 minutes. Using Tackerman amplicon-specific probes (Applied Biosystems, CA, USA) Hamp (CGGCTCTGCAGCCTTG) (SEQ ID NO: 20) for real-time PCR under the following PCR cycle conditions: 95 ° C for 10 minutes; 95 ° C for 15 minutes And 60 ° C for 60 seconds. Hamp's performance was normalized to the GAPDH (CTTCCAGGAGCGAGATCCCGCTAA) (SEQ ID NO: 21) housekeeping gene. Relative gene performance was analyzed using the 2-ΔΔCt method.iPS Of the cell TMPRSS6 Mutation induction and transfection -pCMV6-XL5 TMPRSS6 was purchased from Origene Technologies (Rockville, MD), catalog number SC306623, corresponding to GenBank deposit number NM_153609. This pure line contains a mutation that causes amino acid changes, K253A. Site-directed mutagenesis was performed to restore the amino acid at position 253 to a typical lysine (K). After confirming the recovery, site-directed mutagenesis was performed to introduce the V736A mutation. All mutation-induced responses were performed using the Agilent Technologies QuikChange II XL site-directed mutation induction kit (Santa Clara, CA; Cat. No. 200521). All vectors were sequenced for confirmation. The primer sequences used are: antisense (as) TMPRSS6 E253K GCATGAGGTCCTTGGGGCCCTGCAG (SEQ ID NO: 22); sense (s) TMPRSS6 E253K CTGCAGGGCCCCAAGGACCTCATGC (SEQ ID NO: 23); antisense (as) TMPRSS6 V736A CCTGGTAGCGATAGGCCSEQGCGCTGCATCGCTG : 24); justice (s) TMPRSS6 V736A CCTGTGCAGCGAGGCCTATCGCTACCAGG (SEQ ID NO: 25). 5.14.3.2 Results Human iPS-CMs showed minimally stromal protease-2 at baseline. Cardiomyocytes that imitate the primary dual gene and the secondary dual gene of the homozygote respectively were transfected with a construct that promotes the following constitutive expression:TMPRSS6 The rs855791SNP encodes major protease-2 736A or is encoded by a minor dual gene. Hypaxidine performance is regulated by BMP6 / SMAD and IL-6 / STAT signaling pathways, where both BMP and IL-6 act through their respective receptors to promote increased hypaxidine performance. Casanovas et al.,PLOS Comp. Biol 10 (1): e1003421 (2014). Signaling pathways in vitro-agonists of recombinant BMP2 and IL-6-or BMP2 agonists alone are used to treat major and minor dual iPS cardiomyocytes to model IL-6 content (or signaling) Reduced clinical intervention. Control iPS cells were not treated with agonists. Cell mortality was measured under normal oxygen tension (normal oxygen) and also under conditions of simulated hypoxia followed by simulated reoxygenation (reperfusion). Figure 6A shows the results when cells were treated under normal oxygen content. Performance onlyTMPRSS6 rs855791 secondary dual gene ("736V secondary dual gene") iPS cardiomyocytes are not significantly affected by the elimination of IL-6 signaling ("ns"): Compared to the treatment with BMP2 + IL-6, when used When BMP2 treated cells, the percentage of cell mortality measured as a percentage of trypan blue positive cells did not decrease significantly. In contrast, when IL-6 signaling is eliminated, performanceTMPRSS6 rs855791 iPS cardiomyocytes, which are primarily dual genes, display statistically significantly lower cell death. Figure 6B shows the results when the cells undergo hypoxia followed by reoxygenation. Compared with normoxic conditions, hypoxia / reoxygenation is significantly toxic to iPS cardiomyocytes. Among them, approximately 40% of the primary and secondary dual gene control cells are compared to approximately 20% of the control cells under normoxic conditions. Killed (compare Figure 6B with Figure 6A). In contrast to this increased background toxicity, the secondary dual iPS cardiomyocytes were not significantly affected by the elimination of IL-6 signaling: compared to the treatment with BMP2 + IL-6, the cells died when the cells were treated with BMP2 alone The rate does not decrease significantly. In contrast, when IL-6 signaling is eliminated, performanceTMPRSS6 rs855791 iPS cardiomyocytes, which are primarily dual genes, display statistically significantly lower cell death. 5.14.3.3 Discussion This information enhances the inference derived from the hoc analysis after the clinical trial data in Example 1 and Example 2: Decreased IL-6 signaling can effectively reduce performanceTMPRSS6 rs855791 is predominantly IL-6-mediated toxicity in cardiomyocytes of dual genes, but not in cardiomyocytes that exhibit only secondary dual genes. Without intending to be bound by theory, IL-6, which promotes increased toxicity in the principally dual iPS cardiomyocytes, may result from an IL-6-mediated increase in the expression of hypaxidine, followed by increased iron chelation in the cells, followed by Iron-mediated cytotoxicity. 5.14.4 Example 4: Genotype similar to humanTMPRSS6 rs855791 In the model of cardio-renal syndrome in rats that are primarily dual homozygous, anti-IL-6 therapy is currently used as standard care for patients with chronic kidney disease, such as those selected for the MIMICK study analyzed in Example 1. Patients often suffer from weakened heart function, which is a major contributor to mortality. This second heart injury after the first chronic kidney disease is called type 4 cardiorenal syndrome (type 4 CRS). To test whether anti-IL-6 therapy is availableTMPRSS6 rs855791 is effective in CRS4 patients with at least one replica of the primary gene. As demonstrated by the data in Examples 1 and 3, we use genotypes similar toTMPRSS6 rs855791 is mainly a CRS4 model of human rats with homozygous genes. Figure 7 outlines the study design. At week 0, myocardial infarction was induced in CRS animals. Nephrectomy was performed at week 2. Instead, the control group was subjected to sham surgery. Prior to nephrectomy, various evaluations are performed on the individual. Assessments include measurement of serum creatinine, glomerular filtration rate, 24-hour protein content in urine, echocardiogram, cuff blood pressure, and biomarkers in plasma and urine. Treatment started on day 1 after nephrectomy. Animals were divided into three groups: (i) control therapeutics, (ii) anti-IL-6 therapies, and (iii) standard care therapies. Anti-IL-6 therapy is an anti-IL-6 antibody suitable for rodents. The standard care regimen is the administration of perindopril, an ACE (angiotensin-converting enzyme) inhibitor. At the start of treatment, individuals in all groups were evaluated. Assessments included measurements of serum creatinine, glomerular filtration rate, 24-hour protein content, and biomarkers in plasma. Individuals in all groups were evaluated on days 3 and 7 after nephrectomy. Evaluation includes measurement of serum creatinine and biomarkers in plasma on day 3, and measurement of serum creatinine, glomerular filtration rate, 24-hour protein content, cardiac ultrasound, blood pressure, and blood plasma on day 7. Mark. Individuals were sacrificed at week 6. Prior to sacrifice, various assessments were performed on individuals in all groups. Assessments included measurements of serum creatinine, glomerular filtration rate, 24-hour protein content, blood pressure, plasma biomarkers, cardiac ultrasound, and pressure-volume circuit analysis. Following sacrifice, tissues were also collected from individuals in all groups for histological evaluation (ie, Sirius red staining of heart tissue). Figures 8A-8D show the cardiac ejection fractions of the following in the cardiorenal syndrome model outlined in Figure 7: rats without CRS ("false"), pharmacologically unrelated isotype control antibodies ("isotypes" ") CRS animals treated, CRS animals treated with anti-IL-6 antibodies (" IL-6 ab ") and CRS animals treated with standard care ACE inhibitors (" Peri "). FIG. 8A shows the extent of baseline ejection fraction for all groups two weeks after myocardial infarction but before nephrectomy and before treatment, indicating that experimentally induced myocardial infarction resulted in a significant reduction in cardiac ejection fraction. FIG. 8B is a graph showing the degree of ejection fraction in all groups one week after nephrectomy and one week after treatment. FIG. 8C is a graph showing the degree of ejection fraction in all groups two weeks after nephrectomy and two weeks after treatment. FIG. 8D is a graph showing the degree of ejection fraction in all groups four weeks after nephrectomy and four weeks after treatment. Results are expressed as mean +/- SEM. After 4 weeks of treatment, the treatment group-the group treated with anti-IL-6 and the group treated with standard care ACE inhibitor therapy-all showed a statistically significantly increased degree of ejection fraction compared to the isotype control group (Figure 8D) ) (p <0.001). The degree of anti-IL-6 measured after 4 weeks of treatment and the similar ejection fraction in the standard care group show that anti-IL-6 therapy has an equivalent efficacy to the ACE inhibitor perindopril (standard care therapy), indicating that if borrowed Measured from changes in the ejection fraction of the heart, anti-IL-6 therapy is equivalent to standard nursing therapies in maintaining cardiac function in the cardiorenal syndrome model. Measurements of myocardial contractility (Figure 9) show that anti-IL-6 therapy is also equivalent to standard care therapies using ACE inhibitors. After 4 weeks of treatment, the myocardial contractility of the group treated with anti-IL-6 and standard nursing therapy was significantly increased, which was higher than that of the control and isotype groups. Anti-IL-6 and similar myocardial contractility in the standard care group indicate that anti-IL-6 therapy is equivalent to the ACE inhibitor perindopril in terms of maintaining cardiac function in the cardio-renal syndrome model as measured by contractility Benefits (standard care therapy). Fibrosis measurements of cardiac tissue collected from animals in all groups also confirmed that anti-IL-6 therapy was equivalent to standard care therapy (Figures 10A-10C). Fibrosis in heart tissue is quantified by measuring the percentage of fibrotic tissue area in two areas: the "normal" area and the "fibrotic limit" area. The example "normal" area is indicated by the delineated portion of the tissue section shown in the micrograph in Figure 10A. The illustration in the micrograph shows an enlarged view of the "normal" region, showing that a small portion of the "normal" region has fibrotic tissue. The "fibrotic boundary" area is the tissue area in the "normal" area around the fibrotic tissue. The plots in Figures 10B and 10C show that when measured in the "normal" zone (Figure 10B) or in the "fibrosis limit" zone (Figure 10C), compared to the isotype control group, the anti-IL-6 or standard The cardiac tissue of the individuals in the group treated by the nursing therapy has a significantly reduced percentage of fibrotic tissue area. In addition, the percentages of fibrotic tissue area measured in the anti-IL-6 and standard care therapy groups were similar (both in the "normal" region and the "fibrosis margin" region), indicating that anti-IL-6 has inhibition with ACE Perindopril (standard care therapy) equivalent antifibrotic effect. These data indicate that genotyping is similar to targetingTMPRSS6 rs855791 is an anti-IL-6 agent in vivo model of cardio-renal syndrome in vivo of human animals with homogeneous conjugation genes, which effectively reduces heart damage and restores function. 5.14.5 Example 5: Similar to humans in genotypeTMPRSS6 rs855791 Anti-IL-6 therapy is effective in maintaining cardiac function in an acute myocardial infarction model of a mouse that is primarily dual homozygous, and the data in Examples 2 and 3 indicate that reduced IL-6 content or IL-6 signaling can be reduced Heart failure and death in patients with acute coronary syndromes, but only in patients withTMPRSS6 rs855791 has the largest effect in their patients with at least one replica of the dual gene, and in their patients with elevated serum IL-6 content. Perform rodent studies to determine genotypes similar toTMPRSS6 The role of rs855791 in anti-IL-6 therapy after acute myocardial infarction in human mice with homozygous dual genes. Figures 11A and 11B show data from an in vivo model in which genotypes are similar toTMPRSS6 rs855791 induces myocardial infarction in human mice whose primary dual genes are homozygous. The control group did not receive therapy. The experimental group was treated with anti-mouse IL-6 antibody. FIG. 11A shows that treatment with anti-IL-6 provided a statistically significant improvement in ejection fraction. FIG. 11B shows that treatment with anti-IL-6 provides a statistically significant improvement in measuring contractility as a fraction of cardiac shortening. The data indicate that the anti-IL-6 therapy given immediately after myocardial infarction improved genotype similar to that withTMPRSS6 rs855791 restores left ventricular function in rodents of human patients with primarily dual genes.6. Incorporated by reference All publications, patents, patent applications, and other documents cited in this application are hereby incorporated by reference in their entirety for all purposes, to the same extent as if each individual publication, patent, patent was individually instructed Applications and other literature are incorporated by reference for all purposes.7. Equivalent Although various specific embodiments have been illustrated and described, the above description is not limiting. It should be understood that various changes can be made without departing from the spirit and scope of the invention. Many variations will become apparent to those skilled in the art upon reviewing this specification.

圖 1A 及1B 提供盒狀圖，其展示紅血球生成素(「EPO」)之增加量對於慢性腎病患者(CKD 5期透析個體)中之治療為所需的，該等慢性腎病患者具有升高之血清IL-6含量，及在TMPRSS6 基因中之已知SNP rs855791處的主要對偶基因(核苷酸位置2321處之G或C，編碼在胺基酸位置736處包含丙胺酸之TMPRSS6 多肽；736A)之至少一個複本；但對於具有升高之IL-6含量且針對rs855791TMPRSS6 次要對偶基因(核苷酸位置2321處之T或A，編碼在位置736處具有纈胺酸之TMPRSS6 多肽；736V)為同型接合之慢性腎病患者中的治療不需要。來自針對次要對偶基因為同型接合(A/A)之患者之資料展示於圖1A中；來自具有主要對偶基因(同型接合G/G及異型接合G/A)之至少一個複本之患者之資料收集且展示於圖1B中。基於血清IL-6含量之三分位：「低」位(IL-6 ＜ 5 pg/ml)；「中」位(IL-6 = 5-15 pg/ml)；「最高」位(IL-6 ＞ 15pg/ml)，兩個患者群體中之每一者之進一步分成組。具有誤差棒之盒狀圖在原始資料上方覆疊。基於IL-6含量及基因型兩者，各盒狀圖表示患者組。詳情提供於實例1中。圖 2A 及2B 提供存活曲線，其表明回應於慢性腎病5期透析個體中之升高之IL-6含量，TMPRSS6 rs855791主要對偶基因賦予更高之各種原因之死亡。圖2A展示來自針對次要對偶基因為同型接合(A/A)之患者之資料。圖2B展示來自具有主要對偶基因(同型接合G/G及異型接合G/A)之至少一個複本之患者的資料。使用用於圖1之IL-6含量將各組分成血清IL-6含量之三分位。詳情提供於實例1中。圖 3 為一圖，其展示EPO之增加量對於慢性腎病患者(CKD 5期透析個體)中之療法為所需的，該等慢性腎病患者具有升高之急性期反應物CRP之血清含量且具有TMPRSS6 rs855791主要對偶基因之至少一個複本；但對於具有升高之急性期反應物CRP之血清含量且針對rs855791次要對偶基因為同型接合之慢性腎病患者中的療法不需要。相較於＞ 2 mg/L，各基因型組分成血清CRP含量＜ 2 mg/L。詳情提供於實例1中。圖 4A 及4B 提供曲線圖，其表明在心肌梗塞(「MI」)後之患者中，回應於升高之IL-6含量，TMPRSS6 rs85579 1主要對偶基因賦予更高之各種原因之死亡。圖4A描繪對於針對TMPRSS6 rs855791次要對偶基因為同型接合之群體，相較於MI後之天數(x軸)，死亡事件隨時間推移之累積機率(y軸)。圖4B描繪對於具有TMPRSS6 rs855791主要對偶基因之至少一個複本之群體，死亡事件隨時間推移之累積機率。如所指示，各組分成血清IL-6含量之三分位。在心肌梗塞後一個月量測IL-6含量。在心肌梗塞後一至12個月量測死亡率。詳情提供於實例2中。圖 5A 及5B 提供曲線圖，其表明回應於MI後患者中之升高之IL-6含量，TMPRSS6 rs855791主要對偶基因賦予更高之心臟衰竭(「HF」)風險。圖5A描繪對於針對TMPRSS6 rs855791次要對偶基因為同型接合之群體，相較於MI後之天數(x軸)，HF隨時間推移之累積機率(y軸)。圖5B描繪對於具有TMPRSS6 rs855791主要對偶基因之至少一個複本之群體，HF事件隨時間推移之累積機率。如所指示，各組分成血清IL-6含量之三分位。在心肌梗塞後一個月量測IL-6含量。在心肌梗塞後一至12個月量測HF。詳情提供於實例2中。圖 6A 及6B 展示來自人類iPS細胞之分析的結果，該等細胞已經組成性表現TMPRSS6 rs855791次要對偶基因或主要對偶基因之構築體轉染，且活體外暴露至BMP2+IL-6或僅BMP2時分化成心肌細胞，表明回應於IL-6，TMPRSS6 rs855791主要對偶基因賦予更高之細胞死亡(錐蟲藍(Trypan Blue)陽性)風險。圖6A展示常氧環境中之結果。圖6B展示暴露於低氧條件及再充氧後之結果。資料暗示降低之IL-6暴露應提高具有TMPRSS6 rs855791主要對偶基因之患者中心肌細胞之存活率，但不提高具有TMPRSS6 rs855791次要對偶基因之患者中心肌細胞之存活率。詳情提供於實例3中。圖 7 為展示實例4中所描述之心腎症候群研究之實驗設計的圖式。在基因型地類似於針對TMPRSS6 rs855791主要對偶基因為同型接合之人類之大鼠中誘導CRS4。該圖式展示沿時間線之研究中之各種事件。在研究中，在第0週在大鼠中誘導心肌梗塞(「MI」)。在第2週，在各個體中進行單腎切除(「Nx」)。在腎切除後直至研究結束，在第1天(D1)開始，每3天一次地投與抗IL-6抗體(ab9770，Abcam Plc, UK) (Rx)或同型對照抗體(「IgG」；ab171516，Abcam Plc, UK)。在Nx後直至研究結束，自第1天每天投與標準護理療法(ACE抑制劑-培哚普利(perindopril))。在第6週，將嚙齒動物處死。在『假』對照個體組中不進行MI及Nx。在藉由箭頭指示之時間點下進行嚙齒動物之各種評估。圖 8A-8D 展示在概述於7圖中且詳細地描述於實例4中之心腎症候群模型中,相較於對照(「同型」)處理組及假手術動物，用抗IL-6抗體(「IL-6 ab」)、標準護理ACE抑制劑(培哚普利或「Peri」)治療之大鼠之心臟射血分數。圖8A為展示心肌梗塞後兩週但腎切除之前所有組之基線射血分數程度的繪圖。圖8B為展示腎切除後一週、治療1週後，所有組之射血分數程度的繪圖。圖8C為展示腎切除後兩週、治療2週後，所有組之射血分數程度的繪圖。圖8D為展示腎切除後四週、治療4週後，所有組之射血分數程度的繪圖。結果表述為平均+/-SEM，且表明如藉由心臟射血分數之變化所量測，抗IL-6療法在心腎症候群模型中具有治療功效，等效於標準護理療法。圖 9 描繪一繪圖，其展示在概述於圖7中且詳細地描述於實例4中之心腎症候群模型中，相較於對照(「同型」)處理組，用抗IL-6抗體(「IL-6 ab」)、標準護理(培哚普利或「Peri」)治療之大鼠之心肌收縮性。藉由量測dP/dt最大 (mmHb/msec)，其為心臟內壓力之量度，在結束研究時評估心肌收縮性。展示腎切除後四週、治療4週後所有組之量測結果。結果表述為平均+/-SEM，且表明如藉由用抗IL-6治療之嚙齒動物組中之增加的心肌收縮性所展示，抗IL-6療法具有等效於標準護理療法之治療作用。圖 10A-10C 展示如藉由來自用抗IL-6(「IL-6 Ab」)、標準護理(培哚普利或「Peri」)及對照(「IgG」)治療之嚙齒動物組的心臟組織中纖維化程度所量測，抗IL-6療法具有等效於標準護理療法之抗心腎症候群作用。圖10A為展示用苦味酸天狼星紅(picrosirius-red)染色之心臟組織之組織學部分的顯微圖。分析組織之兩個區：「正常」區及「纖維化界限」區。實例「正常」區藉由組織切片之劃定部分指示。顯微圖中之插圖展示「正常」區之放大視圖，展示「正常」區之小部分具有纖維化組織。「纖維化界限」區為在纖維化組織周圍之「正常」區中之組織區。圖10B為展示來自所有組之組織樣本中，指示為纖維化組織(亦即染色/暗區)之「正常」區之面積百分比的繪圖。圖10C為展示來自所有組之組織樣本中，指示為纖維化組織之「纖維化界限」區之面積百分比的繪圖。結果表述為平均+/-SEM。詳情提供於實例4中。圖 11A 及 11B 展示來自活體內模型之資料，在該模型中，在基因型地類似於針對TMPRSS6 rs855791主要對偶基因為同型接合之人類之小鼠中誘導心肌梗塞。對照組不接受療法。實驗組用抗鼠類IL-6抗體治療。圖11A展示用抗IL-6進行之治療在射血分數方面提供統計學上顯著之提高。圖11B展示用抗IL-6進行之治療在量測為心臟左心室縮短分數之收縮性方面提供統計學上顯著之提高。資料表明在心肌梗塞後立即給出之抗IL-6療法提高了模仿具有TMPRSS6 rs855791主要對偶基因之人類患者之嚙齒動物中左心室的功能恢復。詳情提供於實例5中。 僅出於說明的目的，圖式描繪本發明之各種實施例。熟習此項技術者將自以下論述容易認識到可在不偏離本文中所描述之本發明原則的情況下採用本文中所說明之結構及方法之替代實施例。 Figures 1A and 1B provide box diagrams showing that an increased amount of erythropoietin ("EPO") is required for treatment in patients with chronic kidney disease (CKD stage 5 dialysis individuals), who have an increased serum IL-6, and at the SNP rs855791 known genes in the major TMPRSS6 alleles (nucleotide position 2321 of G or C, comprising encoding alanine at amino acid position 736 of the polypeptide TMPRSS6; 736A) At least one copy; but for the rs855791 TMPRSS6 minor dual gene with elevated IL-6 content (T or A at nucleotide position 2321, encoding a TMPRSS6 polypeptide with valine at position 736; 736V) Treatment is not required in patients with homozygous chronic kidney disease. Data from patients with minor mate genes that are homozygous (A / A) are shown in Figure 1A; data from patients with at least one replica of the major mate genes (homosex G / G and heterozygous G / A) Collected and shown in Figure 1B. Third quartile based on serum IL-6 content: "low" (IL-6 <5 pg / ml); "medium" (IL-6 = 5-15 pg / ml); "highest" (IL- 6> 15 pg / ml), each of the two patient groups was further divided into groups. Box plots with error bars are overlaid on top of the original data. Based on both IL-6 content and genotype, each box plot represents the patient group. Details are provided in Example 1. Figures 2A and 2B provide survival curves that indicate that TMPRSS6 rs855791 predominantly confers higher all-cause death in response to elevated IL-6 levels in individuals with chronic kidney disease stage 5 dialysis. Figure 2A shows data from a patient who is homozygous (A / A) for a secondary dual gene. Figure 2B shows data from a patient with at least one replica of a major dual gene (homozygous G / G and heterozygous G / A). The IL-6 content used in Figure 1 was used to divide the components into tertiles of serum IL-6 content. Details are provided in Example 1. Figure 3 is a graph showing that the increased amount of EPO is required for therapy in patients with chronic kidney disease (CKD stage 5 dialysis individuals) who have elevated serum content of the acute phase reactant CRP and have TMPRSS6 rs855791 is primarily at least one replica of the dual gene; but therapy is not required in patients with chronic kidney disease who have elevated serum levels of the acute phase reactant CRP and are homozygous for the secondary dual gene of rs855791. Compared to> 2 mg / L, the serum CRP content of each genotype component was <2 mg / L. Details are provided in Example 1. Figures 4A and 4B provide graphs showing that in patients after myocardial infarction ("MI"), TMPRSS6 rs85579 1 primarily confers higher deaths on various causes in response to elevated IL-6 levels. FIG. 4A depicts the cumulative probability (y-axis) of death events over time for a population that is homozygous for the TMPRSS6 rs855791 minor dual gene compared to days after MI (x-axis). Figure 4B depicts the cumulative probability of a death event over time for a population with at least one replica of the TMPRSS6 rs855791 major dual gene. As indicated, each component forms the tertile of serum IL-6 content. IL-6 levels were measured one month after myocardial infarction. Mortality was measured one to 12 months after myocardial infarction. Details are provided in Example 2. Figures 5A and 5B provide graphs showing that TMPRSS6 rs855791 confers a higher risk of heart failure ("HF") in response to elevated IL-6 levels in patients after MI. Figure 5A depicts the cumulative probability of HF over time (y-axis) for a population that is homozygous for the TMPRSS6 rs855791 minor dual gene compared to the days after MI (x-axis). Figure 5B depicts the cumulative probability of HF events over time for a population with at least one replica of the TMPRSS6 rs855791 major dual gene. As indicated, each component forms the tertile of serum IL-6 content. IL-6 levels were measured one month after myocardial infarction. HF is measured one to 12 months after myocardial infarction. Details are provided in Example 2. Figures 6A and 6B show the results of analysis from human iPS cells, which cells have constitutively expressed TMPRSS6 rs855791 secondary or major dual gene constructs transfected and exposed to BMP2 + IL-6 or BMP2 only in vitro When differentiated into cardiomyocytes, it was shown that in response to IL-6, TMPRSS6 rs855791 primarily confers a higher risk of cell death (trypan blue positive) on the dual gene. Figure 6A shows the results in a normoxic environment. Figure 6B shows the results after exposure to hypoxic conditions and reoxygenation. The data suggest that reduced exposure to IL-6 should increase the survival rate of cardiomyocytes in patients with the TMPRSS6 rs855791 major dual gene, but not increase the survival rate of cardiomyocytes in patients with the TMPRSS6 rs855791 secondary dual gene. Details are provided in Example 3. FIG. 7 is a diagram showing an experimental design of the cardiorenal syndrome study described in Example 4. FIG. CRS4 is induced in human rats that are genotyped similarly to TMPRSS6 rs855791 whose primary counterpart is homozygous. The diagram shows various events in the study along the timeline. In the study, myocardial infarction ("MI") was induced in rats at week 0. At week 2, a single nephrectomy ("Nx") was performed in each body. After nephrectomy until the end of the study, anti-IL-6 antibody (ab9770, Abcam Plc, UK) (Rx) or isotype control antibody ("IgG"; ab171516) was administered every 3 days beginning on day 1 (D1) , Abcam Plc, UK). After Nx until the end of the study, standard care therapy (ACE inhibitor-perindopril) was administered daily from day 1. At week 6, rodents were sacrificed. MI and Nx were not performed in the "false" control individual group. Various assessments of rodents were performed at the time points indicated by the arrows. Figures 8A-8D are shown in the cardiorenal syndrome model outlined in Figure 7 and described in detail in Example 4, compared to control ("isotype") treatment groups and sham-operated animals with anti-IL-6 antibodies (" IL-6 ab "), standard care ACE inhibitors (perindopril or" Peri ") of the cardiac ejection fraction of rats. FIG. 8A is a graph showing the extent of baseline ejection fractions for all groups two weeks after myocardial infarction but before nephrectomy. FIG. 8B is a graph showing the degree of ejection fraction in all groups one week after nephrectomy and one week after treatment. FIG. 8C is a graph showing the degree of ejection fraction in all groups two weeks after nephrectomy and two weeks after treatment. FIG. 8D is a graph showing the degree of ejection fraction in all groups four weeks after nephrectomy and four weeks after treatment. The results are expressed as mean +/- SEM, and indicate that anti-IL-6 therapy has therapeutic efficacy in the cardio-renal syndrome model as measured by changes in cardiac ejection fraction, which is equivalent to standard care therapy. FIG. 9 depicts a plot shown in the cardiorenal syndrome model outlined in FIG. 7 and described in detail in Example 4, compared to a control ("isotype") treatment group with an anti-IL-6 antibody ("IL -6 ab "), myocardial contractility in rats treated with standard care (perindopril or" Peri "). By measuring the maximum dP / dt (mmHb / msec), which is a measure of intracardiac pressure, myocardial contractility was evaluated at the end of the study. Measurement results of all groups were displayed four weeks after nephrectomy and four weeks after treatment. The results are expressed as mean +/- SEM and indicate that anti-IL-6 therapy has a therapeutic effect equivalent to standard care therapy as demonstrated by increased myocardial contractility in the rodent group treated with anti-IL-6. Figures 10A-10C show heart tissue as from a rodent group treated with anti-IL-6 ("IL-6 Ab"), standard care (Perindopril or "Peri"), and control ("IgG") As measured by the degree of medium fibrosis, anti-IL-6 therapy has an anti-cardiorenal syndrome effect equivalent to standard nursing therapies. FIG. 10A is a micrograph showing a histological portion of cardiac tissue stained with picrosirius-red. Analysis of the two areas of the organization: the "normal" area and the "fibrosis limit" area. The instance "normal" area is indicated by the delineated portion of the tissue section. The illustration in the micrograph shows an enlarged view of the "normal" region, showing that a small portion of the "normal" region has fibrotic tissue. The "fibrotic boundary" area is the tissue area in the "normal" area around the fibrotic tissue. FIG. 10B is a plot showing the percentage of area in the “normal” area of tissue samples from all groups, indicated as fibrotic tissue (ie, stained / dark areas). FIG. 10C is a plot showing the percentage of area in the tissue samples from all groups, indicated as the "fibrotic limit" zone of fibrotic tissue. Results are expressed as mean +/- SEM. Details are provided in Example 4. Figures 11A and 11B show data from an in vivo model in which myocardial infarction is induced in mice that are genotyped similarly to humans whose main counterparts to TMPRSS6 rs855791 are homozygous. The control group did not receive therapy. The experimental group was treated with anti-mouse IL-6 antibody. FIG. 11A shows that treatment with anti-IL-6 provided a statistically significant improvement in ejection fraction. FIG. 11B shows that treatment with anti-IL-6 provided a statistically significant improvement in measuring the contractility of the left ventricular shortening fraction of the heart. The data indicate that the anti-IL-6 therapy given immediately after myocardial infarction improves the recovery of left ventricular function in rodents mimicking human patients with the TMPRSS6 rs855791 major dual gene. Details are provided in Example 5. For illustrative purposes only, various embodiments of the invention are schematically depicted. Those skilled in the art will readily recognize from the following discussion that alternative embodiments of the structures and methods described herein may be employed without departing from the principles of the invention described herein.

Claims (120)

一種治療海帕西啶(hepcidin)介導之病症之方法，其包含： 向患有海帕西啶介導之病症之患者投與治療有效量之IL-6拮抗劑， 其中已確定該患者具有TMPRSS6 rs855791主要對偶基因(major allele)之至少一個複本。A method of treating a hepcidin-mediated disorder, comprising: administering a therapeutically effective amount of an IL-6 antagonist to a patient with a hepcidin-mediated disorder, wherein the patient has been determined to have TMPRSS6 rs855791 is at least one copy of the major allele. 如請求項1之方法，其中先前已確定該患者具有該TMPRSS6 rs855791主要對偶基因之至少一個複本。The method of claim 1, wherein the patient has previously been determined to have at least one copy of the TMPRSS6 rs855791 primary dual gene. 如請求項1之方法，其進一步包含以下之早前步驟： 確定該患者具有該TMPRSS6 rs855791主要對偶基因之至少一個複本。The method of claim 1, further comprising the following earlier steps: determining that the patient has at least one copy of the TMPRSS6 rs855791 major dual gene. 如請求項1至3中任一項之方法，其中該患者具有升高之治療前血清IL-6含量。The method of any one of claims 1 to 3, wherein the patient has an elevated pre-treatment serum IL-6 content. 如請求項1至4中任一項之方法，其中該患者具有升高之治療前血清CRP含量。The method of any one of claims 1 to 4, wherein the patient has an elevated pre-treatment serum CRP content. 如請求項1至5中任一項之方法，其中該海帕西啶介導之病症為慢性疾病貧血。The method of any one of claims 1 to 5, wherein the hypaxidine-mediated condition is anemia of chronic disease. 如請求項6之方法，其中該患者為男性且治療前血紅素(Hb)含量小於14 g/dl。The method of claim 6, wherein the patient is male and has a pre-treatment hemoglobin (Hb) content of less than 14 g / dl. 如請求項7之方法，其中該患者之治療前Hb含量小於13 g/dl。The method of claim 7, wherein the patient's pre-treatment Hb content is less than 13 g / dl. 如請求項8之方法，其中該患者之治療前Hb含量小於12 g/dl。The method of claim 8, wherein the patient's pre-treatment Hb content is less than 12 g / dl. 如請求項9之方法，其中該患者之治療前Hb含量小於11 g/dl。The method of claim 9, wherein the patient's pre-treatment Hb content is less than 11 g / dl. 如請求項6之方法，其中該患者為女性且治療前Hb含量小於12 g/dl。The method of claim 6, wherein the patient is female and has an Hb content of less than 12 g / dl before treatment. 如請求項11之方法，其中該患者之治療前Hb含量小於11 g/dl。The method of claim 11, wherein the patient's pre-treatment Hb content is less than 11 g / dl. 如請求項12之方法，其中該患者之治療前Hb含量小於10 g/dl。The method of claim 12, wherein the patient's pre-treatment Hb content is less than 10 g / dl. 如請求項13之方法，其中該患者之治療前Hb含量小於9 g/dl。The method of claim 13, wherein the patient's pre-treatment Hb content is less than 9 g / dl. 如請求項6至10中任一項之方法，其中該患者為男性且治療前血容比小於40%。The method of any one of claims 6 to 10, wherein the patient is male and the blood volume ratio before treatment is less than 40%. 如請求項15之方法，其中該患者之治療前血容比小於35%。The method of claim 15, wherein the pre-treatment blood volume ratio of the patient is less than 35%. 如請求項16之方法，其中該患者之治療前血容比為30-34%。The method of claim 16, wherein the pre-treatment blood volume ratio of the patient is 30-34%. 11至14中任一項之方法，其中該患者之治療前血容比小於36%。The method of any one of 11 to 14, wherein the pre-treatment blood volume ratio of the patient is less than 36%. 如請求項18之方法，其中該患者之治療前血容比小於30%。The method of claim 18, wherein the patient's pre-treatment blood volume ratio is less than 30%. 如請求項19之方法，其中該患者之治療前血容比為26-29%。The method of claim 19, wherein the pre-treatment blood volume ratio of the patient is 26-29%. 如請求項6至20中任一項之方法，其中該患者已接受至少一次ESA之治療前投與。The method of any one of claims 6 to 20, wherein the patient has received at least one pre-treatment administration of ESA. 如請求項6之方法，其中該患者已接受至少一次ESA之治療前投與且具有正常Hb含量或正常血容比。The method of claim 6, wherein the patient has been administered at least one pre-ESA treatment and has a normal Hb content or normal blood volume ratio. 如請求項6至20中任一項之方法，其中該患者已接受至少一次鐵補充劑之治療前投與。The method of any one of claims 6 to 20, wherein the patient has received at least one pre-treatment administration of an iron supplement. 如請求項6之方法，其中該患者已接受至少一次鐵補充劑之治療前投與且具有正常Hb含量或正常血容比。The method of claim 6, wherein the patient has been administered at least one pre-treatment with an iron supplement and has a normal Hb content or normal blood volume ratio. 如請求項6至20中任一項之方法，其中該患者已接受至少一次血液或紅血球濃厚液(packed red blood cells)之治療前輸注。The method of any of claims 6 to 20, wherein the patient has received at least one pre-treatment infusion of blood or packed red blood cells. 如請求項6之方法，其中該患者已接受至少一次血液或紅血球濃厚液之治療前輸注且具有正常Hb含量或正常血容比。The method of claim 6, wherein the patient has received at least one blood or red blood cell infusion before treatment and has a normal Hb content or a normal blood volume ratio. 如請求項6至26中任一項之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使該患者之Hb含量增加而高於治療前含量之時間期。The method of any one of claims 6 to 26, wherein a dose of the IL-6 antagonist is administered on a time schedule for a period of time sufficient to increase the patient's Hb content above the pre-treatment content. 如請求項6至27中任一項之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使該患者之血容比增加而高於治療前含量之時間期。The method of any one of claims 6 to 27, wherein one dose of the IL-6 antagonist is administered on a time schedule for a period of time sufficient to increase the blood volume ratio of the patient above the pre-treatment level . 如請求項21或22之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使該患者之ESA劑量減少而不使該患者之Hb含量降低至低於接近治療前存在之含量的時間期。The method of claim 21 or 22, wherein one dose of the IL-6 antagonist is administered on a schedule and continued for a period sufficient to reduce the patient's ESA dose without reducing the patient's Hb content below near treatment The time period of the pre-existing content. 如請求項21或22之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使該患者之ESA劑量減少而不使該患者之血容比降低至低於接近治療前存在之含量的時間期。The method of claim 21 or 22, wherein one dose of the IL-6 antagonist is administered on a schedule and for a period sufficient to reduce the patient's ESA dose without reducing the patient's blood volume ratio to less than approximately Time period of content present before treatment. 如請求項21、22、29或30中任一項之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使得該患者之ESA劑量相較於治療前ESA劑量減少至少10%之時間期。The method of any one of claims 21, 22, 29, or 30, wherein one dose of the IL-6 antagonist is administered on a time schedule for a period sufficient to allow the patient's ESA dose to be compared to the pre-treatment ESA dose Reduce the time period by at least 10%. 如請求項31之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使得該患者之ESA劑量相較於治療前ESA劑量減少至少20%之時間期。The method of claim 31, wherein a dose of the IL-6 antagonist dose is administered on a schedule and for a period of time sufficient to reduce the ESA dose of the patient by at least 20% compared to the ESA dose before treatment. 如請求項32之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使得該患者之ESA劑量相較於治療前ESA劑量減少至少50%之時間期。The method of claim 32, wherein one dose of the IL-6 antagonist is administered on a schedule and for a period of time sufficient to reduce the patient's ESA dose by at least 50% compared to the pre-treatment ESA dose. 如請求項6至33中任一項之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以逆轉功能性鐵缺乏之時間期。The method of any one of claims 6 to 33, wherein one dose of the IL-6 antagonist is administered on a time schedule for a period of time sufficient to reverse functional iron deficiency. 如請求項6至34中任一項之方法，其中該慢性疾病為慢性腎病(CKD)。The method of any one of claims 6 to 34, wherein the chronic disease is chronic kidney disease (CKD). 如請求項35之方法，其中該患者具有KDOQI 1期慢性腎病、KDOQI 2期慢性腎病、KDOQI 3期慢性腎病、KDOQI 4期慢性腎病或KDOQI 5期慢性腎病。The method of claim 35, wherein the patient has KDOQI stage 1 chronic kidney disease, KDOQI stage 2 chronic kidney disease, KDOQI stage 3 chronic kidney disease, KDOQI stage 4 chronic kidney disease, or KDOQI stage 5 chronic kidney disease. 如請求項36之方法，其中該患者具有KDOQI 5期慢性腎病。The method of claim 36, wherein the patient has KDOQI stage 5 chronic kidney disease. 如請求項35之方法，其中該患者具有心腎症候群(CRS)。The method of claim 35, wherein the patient has a cardio-renal syndrome (CRS). 如請求項38之方法，其中該患者具有第4型CRS。The method of claim 38, wherein the patient has a type 4 CRS. 如請求項35至39中任一項之方法，其中該患者已接受至少一次治療前透析治療。The method of any one of claims 35 to 39, wherein the patient has received at least one pre-treatment dialysis treatment. 如請求項35至40中任一項之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使心血管(CV)死亡率相較於年齡匹配且疾病匹配之歷史對照組降低之時間期。The method of any one of claims 35 to 40, wherein one dose of the IL-6 antagonist is administered on a time schedule for a period sufficient to cause cardiovascular (CV) mortality compared to age-matched and disease-matched The period of decline in the historical control group. 如請求項6至34中任一項之方法，其中該慢性疾病為慢性發炎疾病。The method of any one of claims 6 to 34, wherein the chronic disease is a chronic inflammatory disease. 如請求項42之方法，其中該慢性發炎疾病為類風濕性關節炎(RA)。The method of claim 42, wherein the chronic inflammatory disease is rheumatoid arthritis (RA). 如請求項43之方法，其中該患者之治療前DAS28得分大於5.1。The method of claim 43, wherein the patient's pre-treatment DAS28 score is greater than 5.1. 如請求項43之方法，其中該患者之治療前DAS28得分為3.2至5.1。The method of claim 43, wherein the patient's pre-treatment DAS28 score is 3.2 to 5.1. 如請求項43之方法，其中該患者之治療前DAS28得分小於2.6。The method of claim 43, wherein the patient's pre-treatment DAS28 score is less than 2.6. 如請求項43之方法，其中該患者之治療前RA為中度活動性至重度活動性。The method of claim 43, wherein the pre-treatment RA of the patient is moderately active to severely active. 如請求項43至47中任一項之方法，其中該患者已接受至少一次甲胺喋呤(methotrexate)之治療前投與。The method of any one of claims 43 to 47, wherein the patient has received at least one pre-treatment dose of methotrexate. 如請求項43至48中任一項之方法，其中該患者已接受至少一次TNFα拮抗劑之治療前投與。The method of any one of claims 43 to 48, wherein the patient has received at least one pre-treatment administration of a TNFα antagonist. 如請求項49之方法，其中該TNFα拮抗劑選自由以下組成之群：依那西普(etanercept)、阿達木單抗(adalimumab)、英利昔單抗(infliximab)、賽妥珠單抗(certolizumab)及戈利木單抗(golimu-mab)。The method of claim 49, wherein the TNFα antagonist is selected from the group consisting of etanercept, adalimumab, infliximab, and certolizumab ) And golimu-mab. 如請求項43至47中任一項之方法，其中該患者已接受至少一次IL-6拮抗劑之治療前投與。The method of any one of claims 43 to 47, wherein the patient has received at least one pre-treatment administration of an IL-6 antagonist. 如請求項51之方法，其中該治療前IL-6拮抗劑為托珠單抗(tocilizumab)。The method of claim 51, wherein the pre-treatment IL-6 antagonist is tocilizumab. 如請求項51之方法，其中該治療前IL-6拮抗劑為托法替尼(tofacitinib)。The method of claim 51, wherein the pre-treatment IL-6 antagonist is tofacitinib. 如請求項51至53中任一項之方法，其中該治療IL-6拮抗劑為MEDI5117。The method of any one of claims 51 to 53, wherein the therapeutic IL-6 antagonist is MEDI5117. 如請求項42之方法，其中該慢性發炎疾病選自由以下組成之群：幼年期特發性關節炎、僵直性脊椎炎、斑狀牛皮癬、牛皮癬性關節炎、發炎性腸病、克羅恩氏病(Crohn's disease)及潰瘍性結腸炎。The method of claim 42, wherein the chronic inflammatory disease is selected from the group consisting of juvenile idiopathic arthritis, ankylosing spondylitis, plaque psoriasis, psoriasis arthritis, inflammatory bowel disease, Crohn's Crohn's disease and ulcerative colitis. 如請求項6至34中任一項之方法，其中該慢性疾病為癌症。The method of any one of claims 6 to 34, wherein the chronic disease is cancer. 如請求項56之方法，其中該癌症選自由以下組成之群：實體腫瘤、小細胞肺癌、非小細胞肺癌、血液癌、多發性骨髓瘤、白血病、慢性淋巴細胞白血病(CLL)、慢性骨髓性白血病(CML)、淋巴瘤、霍奇金氏淋巴瘤(Hodgkin's lymphoma)及肝腺瘤。The method of claim 56, wherein the cancer is selected from the group consisting of solid tumors, small cell lung cancer, non-small cell lung cancer, blood cancer, multiple myeloma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid Leukemia (CML), lymphoma, Hodgkin's lymphoma, and hepatic adenoma. 如請求項6至34中任一項之方法，其中該慢性疾病為慢性感染。The method of any one of claims 6 to 34, wherein the chronic disease is a chronic infection. 如請求項6至34中任一項之方法，其中該慢性疾病為充血性心臟衰竭(CHF)。The method of any one of claims 6 to 34, wherein the chronic disease is congestive heart failure (CHF). 如請求項1至5中任一項之方法，其中該海帕西啶介導之病症為鐵難治性缺鐵性貧血(IRIDA)。The method of any one of claims 1 to 5, wherein the hypaxidine-mediated condition is iron-refractory iron deficiency anemia (IRIDA). 如請求項1至5中任一項之方法，其中該海帕西啶介導之病症為急性冠狀動脈症候群。The method of any one of claims 1 to 5, wherein the hypaxidine-mediated condition is an acute coronary syndrome. 如請求項61之方法，其中該患者在第一次投與IL-6拮抗劑之前60天內已罹患心肌梗塞(MI)。The method of claim 61, wherein the patient has suffered a myocardial infarction (MI) within 60 days before the first administration of the IL-6 antagonist. 如請求項62之方法，其中該患者在第一次投與IL-6拮抗劑之前30天內已罹患MI。The method of claim 62, wherein the patient has developed MI within 30 days before the first administration of the IL-6 antagonist. 如請求項63之方法，其中該患者在第一次投與IL-6拮抗劑之前48小時內已罹患MI。The method of claim 63, wherein the patient has developed MI within 48 hours before the first administration of the IL-6 antagonist. 如請求項64之方法，其中該患者在第一次投與IL-6拮抗劑之前24小時內已罹患MI。The method of claim 64, wherein the patient has developed MI within 24 hours before the first administration of the IL-6 antagonist. 如請求項61至65中任一項之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以相較於治療前程度改良心肌收縮性之時間期。The method of any one of claims 61 to 65, wherein one dose of the IL-6 antagonist is administered on a time schedule for a period of time sufficient to improve myocardial contractility compared to the degree before treatment. 如請求項61至66中任一項之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以相較於治療前程度改良心臟射血分數之時間期。The method of any one of claims 61 to 66, wherein one dose of the IL-6 antagonist is administered on a time schedule for a period of time sufficient to improve the cardiac ejection fraction compared to the level before treatment. 如請求項66之方法，其進一步包含確定該患者對於該TMPRSS6 rs855791次要對偶基因為同型接合之早前步驟。The method of claim 66, further comprising an earlier step of determining that the patient is homozygous for the TMPRSS6 rs855791 minor dual gene. 一種治療無慢性發炎貧血之患者的IL-6介導之發炎病症之方法，其包含： 向患有IL-6介導之發炎病症的無貧血患者投與治療有效量之IL-6拮抗劑， 其中已確定該患者具有TMPRSS6 rs855791主要對偶基因之至少一個複本。A method for treating an IL-6-mediated inflammatory condition in a patient without chronic inflammatory anemia, comprising: administering a therapeutically effective amount of an IL-6 antagonist to a non-anemia patient with an IL-6-mediated inflammatory condition, It has been determined that the patient has at least one copy of the TMPRSS6 rs855791 primary dual gene. 如請求項69之方法，其中先前已確定該患者具有該TMPRSS6 rs855791主要對偶基因之至少一個複本。The method of claim 69, wherein the patient has previously been determined to have at least one copy of the TMPRSS6 rs855791 major dual gene. 如請求項69之方法，其進一步包含確定該患者具有該TMPRSS6 rs855791主要對偶基因之至少一個複本之早前步驟。The method of claim 69, further comprising an earlier step of determining that the patient has at least one copy of the TMPRSS6 rs855791 major dual gene. 如請求項1至71中任一項之方法，其中該患者具有升高之治療前血清IL-6含量。The method of any one of claims 1 to 71, wherein the patient has an elevated pre-treatment serum IL-6 content. 如請求項72之方法，其中該患者之治療前血清IL-6含量大於2.5 pg/ml。The method of claim 72, wherein the patient's pre-treatment serum IL-6 content is greater than 2.5 pg / ml. 如請求項73之方法，其中該患者之治療前血清IL-6含量大於5 pg/ml。The method of claim 73, wherein the patient's pre-treatment serum IL-6 content is greater than 5 pg / ml. 如請求項74之方法，其中該患者之治療前血清IL-6含量大於7.5 pg/ml。The method of claim 74, wherein the patient's pre-treatment serum IL-6 content is greater than 7.5 pg / ml. 如請求項75之方法，其中該患者之治療前血清IL-6含量大於10 pg/ml。The method of claim 75, wherein the patient's pre-treatment serum IL-6 content is greater than 10 pg / ml. 如請求項76之方法，其中該患者之治療前血清IL-6含量大於12.5 pg/ml。The method of claim 76, wherein the patient's pre-treatment serum IL-6 content is greater than 12.5 pg / ml. 如請求項72至77中任一項之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使該患者之血清中之游離IL-6含量降低而低於治療前含量之時間期。The method of any one of claims 72 to 77, wherein one dose of the IL-6 antagonist is administered on a time schedule and for a period sufficient to reduce the free IL-6 content in the patient's serum to less than the treatment The period of time before the content. 如請求項78之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使游離IL-6含量相較於治療前含量降低至少10%之時間期。The method of claim 78, wherein one dose of the IL-6 antagonist is administered on a time schedule for a period of time sufficient to reduce the free IL-6 content by at least 10% compared to the pre-treatment content. 如請求項79之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使該患者之血清中之游離IL-6含量相較於治療前含量降低至少20%之時間期。The method of claim 79, wherein one dose of the IL-6 antagonist is administered on a schedule and for a period sufficient to reduce the free IL-6 content in the patient's serum by at least 20% compared to the pre-treatment content. Time period. 如請求項80之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使該患者之血清中之游離IL-6含量相較於治療前含量降低至少50%之時間期。The method of claim 80, wherein one dose of the IL-6 antagonist is administered on a schedule and for a period sufficient to reduce the free IL-6 content in the patient's serum by at least 50% compared to the pre-treatment content. Time period. 如請求項1至81中任一項之方法，其中該患者具有升高之治療前C反應蛋白(CRP)含量。The method of any one of claims 1 to 81, wherein the patient has an elevated pre-treatment C-reactive protein (CRP) content. 如請求項82之方法，其中該患者之治療前CRP含量大於2 mg/ml。The method of claim 82, wherein the patient's pre-treatment CRP content is greater than 2 mg / ml. 如請求項83之方法，其中該患者之治療前CRP含量大於3 mg/ml。The method of claim 83, wherein the patient's pre-treatment CRP content is greater than 3 mg / ml. 如請求項84之方法，其中該患者之治療前CRP含量大於5 mg/ml。The method of claim 84, wherein the patient's pre-treatment CRP content is greater than 5 mg / ml. 如請求項85之方法，其中該患者之治療前CRP含量大於7.5 mg/ml。The method of claim 85, wherein the patient's pre-treatment CRP content is greater than 7.5 mg / ml. 如請求項86之方法，其中該患者之治療前CRP含量大於10 mg/ml。The method of claim 86, wherein the pre-treatment CRP content of the patient is greater than 10 mg / ml. 如請求項82至87中任一項之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使該患者之CRP含量降低而低於治療前含量之時間期。The method of any one of claims 82 to 87, wherein one dose of the IL-6 antagonist is administered on a time schedule for a period of time sufficient to reduce the CRP content of the patient below the pre-treatment level. 如請求項88之方法，其中按時程投與一劑該IL-6拮抗劑劑量，且持續一段足以使該患者之CRP含量相較於治療前含量降低至少50%之時間期。The method of claim 88, wherein one dose of the IL-6 antagonist is administered on a schedule and for a period of time sufficient to reduce the patient's CRP content by at least 50% compared to the pre-treatment content. 如請求項1至89中任一項之方法，其中使用TaqMan®即時PCR分析，已確定該患者具有該TMPRSS6 rs855791主要對偶基因之至少一個複本。The method of any one of claims 1 to 89, wherein using TaqMan® real-time PCR analysis, it has been determined that the patient has at least one copy of the TMPRSS6 rs855791 major dual gene. 如請求項1至90中任一項之方法，其中該IL-6拮抗劑為抗IL-6抗體或其抗原結合片段或衍生物。The method according to any one of claims 1 to 90, wherein the IL-6 antagonist is an anti-IL-6 antibody or an antigen-binding fragment or derivative thereof. 如請求項91之方法，其中該抗IL-6抗體或抗原結合片段或衍生物對人類IL-6之結合性具有小於100 nM之KD 。The method of claim 91, wherein the anti-IL-6 antibody or antigen-binding fragment or derivative has a K D of less than 100 nM for binding to human IL-6. 如請求項92之方法，其中該抗體或抗原結合片段或衍生物對人類IL-6之結合性具有小於50 nM之KD 。The method according to item 92 of the request, wherein the antibody or antigen-binding fragment or derivative thereof having a K D of less than 50 nM for IL-6 binding of human. 如請求項93之方法，其中該抗體或抗原結合片段或衍生物對人類IL-6之結合性具有小於10 nM之KD 。The method according to item 93 requested, wherein the antibody or antigen-binding fragment or derivative thereof having a K D of less than 10 nM for IL-6 binding of human. 如請求項94之方法，其中該抗體或抗原結合片段或衍生物對人類IL-6之結合性具有小於1 nM之KD 。The method of claim 94, wherein the antibody or antigen-binding fragment or derivative has a K D of less than 1 nM for binding to human IL-6. 如請求項91至95中任一項之方法，其中該抗IL-6抗體或抗原結合片段或衍生物在靜脈內投與後具有至少7天之消除半衰期。The method of any one of claims 91 to 95, wherein the anti-IL-6 antibody or antigen-binding fragment or derivative has an elimination half-life of at least 7 days after intravenous administration. 如請求項96之方法，其中該抗IL-6抗體或抗原結合片段或衍生物在靜脈內投與後具有至少14天之消除半衰期。The method of claim 96, wherein the anti-IL-6 antibody or antigen-binding fragment or derivative has an elimination half-life of at least 14 days after intravenous administration. 如請求項97之方法，其中該抗IL-6抗體或抗原結合片段或衍生物在靜脈內投與後具有至少21天之消除半衰期。The method of claim 97, wherein the anti-IL-6 antibody or antigen-binding fragment or derivative has an elimination half-life of at least 21 days after intravenous administration. 如請求項98之方法，其中該抗IL-6抗體或抗原結合片段或衍生物在靜脈內投與後具有至少30天之消除半衰期。The method of claim 98, wherein the anti-IL-6 antibody or antigen-binding fragment or derivative has an elimination half-life of at least 30 days after intravenous administration. 如請求項91至99中任一項之方法，其中該IL-6拮抗劑為全長單株抗IL-6抗體。The method of any one of claims 91 to 99, wherein the IL-6 antagonist is a full-length monoclonal anti-IL-6 antibody. 如請求項100之方法，其中該抗體為IgG1或IgG4抗體。The method of claim 100, wherein the antibody is an IgG1 or IgG4 antibody. 如請求項101之方法，其中該抗體為IgG1抗體。The method of claim 101, wherein the antibody is an IgG1 antibody. 如請求項91至102中任一項之方法，其中該抗IL-6抗體或抗原結合片段或衍生物為完全人類的。The method of any one of claims 91 to 102, wherein the anti-IL-6 antibody or antigen-binding fragment or derivative is completely human. 如請求項91至102中任一項之方法，其中該抗IL-6抗體或抗原結合片段或衍生物為人類化的。The method of any one of claims 91 to 102, wherein the anti-IL-6 antibody or antigen-binding fragment or derivative is humanized. 如請求項91至104中任一項之方法，其中該抗IL-6抗體或抗原結合片段或衍生物包含MED5117之所有六個可變區CDR。The method of any one of claims 91 to 104, wherein the anti-IL-6 antibody or antigen-binding fragment or derivative comprises all six variable region CDRs of MED5117. 如請求項105之方法，其中該抗體包含MED5117之VH及VL。The method of claim 105, wherein the antibody comprises VH and VL of MED5117. 如請求項106之方法，其中該抗體為MED5117。The method of claim 106, wherein the antibody is MED5117. 如請求項91至104中任一項之方法，其中該抗IL-6抗體或抗原結合片段或衍生物包含選自由以下組成之群的抗體之所有六個可變區CDR：司妥昔單抗(siltuximab)、格里林祖單抗(gerilimzu-mab)、思魯庫單抗(sirukumab)、克拉雜奇單抗(clazakizumab)、奧諾奇單抗(olokizumab)、艾思莫單抗(elsilimomab)、VX30 (VOP-R003；Vaccinex)、EB-007 (EBI-029；Eleven Bio)、ARGX-109 (ArGEN-X)、FM101 (Femta Pharmaceuticals, Lonza)及ALD518/BMS-945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb)。The method of any one of claims 91 to 104, wherein the anti-IL-6 antibody or antigen-binding fragment or derivative comprises all six variable region CDRs selected from the group consisting of antibodies: stuximab (siltuximab), gerilimzu-mab, sirukumab, clazakizumab, olokizumab, elsilimomab ), VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), ARGX-109 (ArGEN-X), FM101 (Femta Pharmaceuticals, Lonza), and ALD518 / BMS-945429 (Alder Biopharmaceuticals, Bristol -Myers Squibb). 如請求項108之方法，其中該抗IL-6抗體或抗原結合片段或衍生物包含選自由以下組成之群的抗體之重鏈V區及輕鏈V區：司妥昔單抗、格里林祖單抗、思魯庫單抗、克拉雜奇單抗、奧諾奇單抗、VX30 (VOP-R003；Vaccinex)、EB-007 (EBI-029；Eleven Bio)、ARGX-109 (ArGEN-X)、FM101 (Femta Pharmaceuticals, Lonza)及ALD518/BMS-945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb)。在特定實施例中，該抗IL-6抗體為選自由以下組成之群的抗體：司妥昔單抗、格里林祖單抗、思魯庫單抗、克拉雜奇單抗、奧諾奇單抗、VX30 (VOP-R003；Vaccinex)、EB-007 (EBI-029；Eleven Bio)、ARGX-109 (ArGEN-X)、FM101 (Femta Pharmaceuticals, Lonza)及ALD518/BMS-945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb)。The method of claim 108, wherein the anti-IL-6 antibody or antigen-binding fragment or derivative comprises a heavy chain V region and a light chain V region of an antibody selected from the group consisting of: stuximab, grelin Zulmuzumab, Siluzumab, Clazacizumab, Onochumab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), ARGX-109 (ArGEN-X ), FM101 (Femta Pharmaceuticals, Lonza) and ALD518 / BMS-945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb). In a specific embodiment, the anti-IL-6 antibody is an antibody selected from the group consisting of: stuximab, grelimizumab, siluzumab, clazazumab, onoch Mab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), ARGX-109 (ArGEN-X), FM101 (Femta Pharmaceuticals, Lonza), and ALD518 / BMS-945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb). 如請求項109之方法，其中該抗IL-6抗體或抗原結合片段或衍生物為選自由以下組成之群的抗體：司妥昔單抗、格里林祖單抗、思魯庫單抗、克拉雜奇單抗、奧諾奇單抗、VX30 (VOP-R003；Vaccinex)、EB-007 (EBI-029；Eleven Bio)、ARGX-109 (ArGEN-X)、FM101 (Femta Pharmaceuticals, Lonza)及ALD518/ BMS-945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb)。在特定實施例中，該抗IL-6抗體為選自由以下組成之群的抗體：司妥昔單抗、格里林祖單抗、思魯庫單抗、克拉雜奇單抗、奧諾奇單抗、VX30 (VOP-R003；Vaccinex)、EB-007 (EBI-029；Eleven Bio)、ARGX-109 (ArGEN-X)、FM101 (Femta Pharmaceu-ticals, Lonza)及ALD518/BMS-945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb)。The method of claim 109, wherein the anti-IL-6 antibody or antigen-binding fragment or derivative is an antibody selected from the group consisting of: stuximab, grilimuzumab, siluzumab, Crazacizumab, Onochizumab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), ARGX-109 (ArGEN-X), FM101 (Femta Pharmaceuticals, Lonza), and ALD518 / BMS-945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb). In a specific embodiment, the anti-IL-6 antibody is an antibody selected from the group consisting of: stuximab, grelimizumab, siluzumab, clazazumab, onoch MAb, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), ARGX-109 (ArGEN-X), FM101 (Femta Pharmaceu-ticals, Lonza), and ALD518 / BMS-945429 (Alder Biopharmaceuticals, Bristol-Myers Squibb). 如請求項91至99中任一項之方法，其中該IL-6拮抗劑為單域抗體、VHH奈米抗體(Nanobody)、Fab或scFv。The method according to any one of claims 91 to 99, wherein the IL-6 antagonist is a single domain antibody, a VHH nanobody, a Fab, or a scFv. 如請求項1至90中任一項之方法，其中該IL-6拮抗劑為抗IL-6R抗體或其抗原結合片段或衍生物。The method according to any one of claims 1 to 90, wherein the IL-6 antagonist is an anti-IL-6R antibody or an antigen-binding fragment or derivative thereof. 如請求項112之方法，其中該抗IL-6R抗體、抗原結合片段或衍生物為托珠單抗。The method of claim 112, wherein the anti-IL-6R antibody, antigen-binding fragment or derivative is tocilizumab. 如請求項112之方法，其中該抗IL-6R抗體、抗原結合片段或衍生物為夫巴利珠單抗(vobarilizumab)。The method of claim 112, wherein the anti-IL-6R antibody, antigen-binding fragment or derivative is vobalimizumab. 如請求項1至90中任一項之方法，其中該IL-6拮抗劑為JAK抑制劑。The method of any one of claims 1 to 90, wherein the IL-6 antagonist is a JAK inhibitor. 如請求項115之方法，其中該JAK抑制劑選自由以下組成之群：托法替尼(tofacitinib)(Xeljanz)、得森替尼(decernotinib)、盧佐替尼(ruxolitinib)、尤帕達替尼(upadacitinib)、巴瑞替尼(barici-tinib)、斐哥替尼(filgotinib)、來妥替尼(lestaurtinib)、帕瑞替尼(pacritinib)、皮非替尼(peficitinib)、INCB-039110、ABT-494、INCB-047986及AC-410。The method of claim 115, wherein the JAK inhibitor is selected from the group consisting of tofacitinib (Xeljanz), decernotinib, ruxolitinib, yupadatin Upadacitinib, barici-tinib, filgotinib, lestaurtinib, pacritinib, peficitinib, INCB-039110 , ABT-494, INCB-047986, and AC-410. 如請求項1至90中任一項之方法，其中該IL-6拮抗劑為STAT3抑制劑。The method of any one of claims 1 to 90, wherein the IL-6 antagonist is a STAT3 inhibitor. 如請求項91至114中任一項之方法，其中該IL-6拮抗劑係非經腸投與。The method of any one of claims 91 to 114, wherein the IL-6 antagonist is administered parenterally. 如請求項118之方法，其中該IL-6拮抗劑係經皮下投與。The method of claim 118, wherein the IL-6 antagonist is administered subcutaneously. 如請求項115至116中任一項之方法，其中該IL-6拮抗劑係經口投與。The method of any one of claims 115 to 116, wherein the IL-6 antagonist is administered orally.
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